VCV000004288.115 - ClinVar

NM_000157.4(GBA1):c.1448T>C (p.Leu483Pro)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(45)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic; risk factor

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

This variant is part of a Haplotype

NM_001005741.2(GBA1):c.[1448T>C;1483G>C;1497G>C]

This variant is part of 2 Genotypes

Identifiers

NM_000157.4(GBA1):c.1448T>C (p.Leu483Pro)

Variation ID: 4288 Accession: VCV000004288.115

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q22 1: 155235252 (GRCh38) [ NCBI UCSC ] 1: 155205043 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 4, 2013	Nov 24, 2024	Aug 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000157.4:c.1448T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000148.2:p.Leu483Pro	missense
NM_000157.3:c.[1448T>C]
NM_001005741.3:c.1448T>C	NP_001005741.1:p.Leu483Pro	missense
NM_001005742.2:c.1448T>C
NM_001005742.3:c.1448T>C	NP_001005742.1:p.Leu483Pro	missense
NM_001171811.2:c.1187T>C	NP_001165282.1:p.Leu396Pro	missense
NM_001171812.2:c.1301T>C	NP_001165283.1:p.Leu434Pro	missense
NC_000001.11:g.155235252A>G
NC_000001.10:g.155205043A>G
NG_009783.1:g.14446T>C
NG_042867.1:g.1714A>G
	P04062:p.Leu483Pro

... more HGVS ... less HGVS

Protein change

L483P, L396P, L434P

Other names

L444P

Canonical SPDI

NC_000001.11:155235251:A:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00339 (G)

Allele frequency Help The frequency of the allele represented by this VCV record.

Exome Aggregation Consortium (ExAC) 0.00310

1000 Genomes Project 0.00339

Links

ClinGen: CA116765 Genetic Testing Registry (GTR): GTR000321628 Genetic Testing Registry (GTR): GTR000325400 Genetic Testing Registry (GTR): GTR000556544 UniProtKB: P04062#VAR_003321 OMIM: 606463.0001 OMIM: 606463.0009 dbSNP: rs421016 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
GBA1		-	-	GRCh38 GRCh38 GRCh37	32	408
LOC106627981	-	-	-	GRCh38 GRCh38	-	362

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Gaucher disease type III	Pathogenic (3)	criteria provided, single submitter	-	RCV000004510.20
Gaucher disease type II	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Jul 7, 2020	RCV000004509.22
Parkinson disease, late-onset	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jan 3, 2022	RCV000004512.27
Gaucher disease type I	Pathogenic (9)	criteria provided, multiple submitters, no conflicts	Nov 26, 2021	RCV000004511.34
Dementia, Lewy body, susceptibility to	risk factor (1)	no assertion criteria provided	Oct 1, 2013	RCV000004513.16
Gaucher disease	Pathogenic (7)	criteria provided, multiple submitters, no conflicts	Mar 5, 2022	RCV000020150.25
not provided	Pathogenic (9)	criteria provided, multiple submitters, no conflicts	Aug 1, 2024	RCV000413257.60
Hypomimic face Movement disorder Parkinsonian disorder Resting tremor Thoracolumbar scoliosis	risk factor (1)	criteria provided, single submitter	Jan 1, 2017	RCV000626625.10
Gaucher disease type I Gaucher disease type II Gaucher disease type III Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome	Pathogenic (1)	criteria provided, single submitter	-	RCV001004112.9
Gaucher disease perinatal lethal	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jan 21, 2020	RCV001197164.14
Gaucher disease perinatal lethal Gaucher disease type I Gaucher disease type II Gaucher disease type III Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome Lewy body dementia Parkinson disease, late-onset	Pathogenic (1)	criteria provided, single submitter	Feb 8, 2022	RCV002476924.8
not specified	Pathogenic (1)	criteria provided, single submitter	Feb 1, 2022	RCV004018555.1
GBA1-related disorder	Pathogenic (1)	no assertion criteria provided	Aug 29, 2024	RCV003398445.6
Lewy body dementia	Pathogenic (1)	criteria provided, single submitter	Mar 17, 2024	RCV003987311.3
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Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
risk factor (Jan 01, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Movement disorder Hypomimic face Parkinsonian disorder Resting tremor Thoracolumbar scoliosis Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV000747326.1 First in ClinVar: May 12, 2018 Last updated: May 12, 2018
Pathogenic (Feb 23, 2017)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000111209.8 First in ClinVar: Jan 17, 2014 Last updated: Dec 15, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GBA Number of individuals with the variant: 74 Sex: mixed
Pathogenic (Oct 30, 2019)	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019)) Method: clinical testing	Gaucher disease type I Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV001194224.2 First in ClinVar: Apr 06, 2020 Last updated: Jul 06, 2020	Publications: PubMed (5) PubMed: 2880291‚ 15146461‚ 21106416‚ 27123474‚ 9375849 Comment: NM_001005741.2(GBA):c.1448T>C(L483P, aka L444P) is classified as pathogenic in the context of Gaucher disease. The L483P variant can be associated with either Type 1, 2 or … (more) NM_001005741.2(GBA):c.1448T>C(L483P, aka L444P) is classified as pathogenic in the context of Gaucher disease. The L483P variant can be associated with either Type 1, 2 or 3 Gaucher disease. Sources cited for classification include the following: PMID 2880291, 15146461, 21106416, 27123474 and 9375849. Classification of NM_001005741.2(GBA):c.1448T>C(L483P, aka L444P) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. (less)
Pathogenic (Nov 02, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Gaucher disease perinatal lethal Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001367800.2 First in ClinVar: Jul 06, 2020 Last updated: Dec 12, 2020	Comment: This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PM1,PM5,PP3,PP5,PS1,PS3.
Pathogenic (Apr 15, 2021)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Gaucher disease Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000697583.2 First in ClinVar: Apr 04, 2013 Last updated: May 01, 2021	Publications: PubMed (5) PubMed: 14757438‚ 24022302‚ 15605411‚ 23430543‚ 23719189 Comment: Variant summary: GBA c.1448T>C (p.Leu483Pro) results in a non-conservative amino acid change located in the Glycosyl hydrolase family 30, beta sandwich domain (IPR033452) of the … (more) Variant summary: GBA c.1448T>C (p.Leu483Pro) results in a non-conservative amino acid change located in the Glycosyl hydrolase family 30, beta sandwich domain (IPR033452) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0013 in 250058 control chromosomes (gnomAD). c.1448T>C has been reported in the literature in multiple individuals affected with Gaucher Disease (Miocic_ 2005, Malini_2013, Siebert_2013, Tammachote_2013). These data indicate that the variant is very likely to be associated with disease. Functional studies report the variant effect results in decreasing GBA enzyme activity in transfected cells (Alfonso__2004, Malini_2013). 12 ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=11) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (May 18, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Gaucher disease type I Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV001653493.1 First in ClinVar: Jun 08, 2021 Last updated: Jun 08, 2021	Sex: mixed
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Gaucher disease type I Affected status: yes Allele origin: inherited	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India Accession: SCV002053774.1 First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022
Pathogenic (Jan 03, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Parkinson disease, late-onset Affected status: yes Allele origin: germline	3billion Accession: SCV002058438.1 First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022	Publications: PMID:28969384 PMID:28969384 PMID:15146461 PMID:15146461 Comment: Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000004288, PS1_S).Functional studies provide … (more) Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000004288, PS1_S).Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 28969384, 15146461, PS3_S). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000093449, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.858, 3CNET: 0.995, PP3_P). A missense variant is a common mechanism associated with Parkinson disease (PP2_P). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Abnormal brain morphology (present) , Parkinsonian disorder (present)
Pathogenic (Mar 21, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	AiLife Diagnostics, AiLife Diagnostics Accession: SCV002502911.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022	Publications: PubMed (75): PubMed: 2880291 33402667 25249066 21228398 21106416 22623374 27094865 18347322 34275192 29471591 33083013 25535748 32014045 21742527 17875915 21472771 33473340 22192918 32618053 20816920 30146349 32883051 33763395 27865684 25333069 29487000 22220748 23635853 30548430 26096741 8294487 27896091 16967369 30941926 29934114 30456712 33176831 22975760 11336129 22227073 29625627 24126159 33977031 16293621 27717005 22160715 24195576 24022302 23676350 20004703 24020503 27153395 21700325 29602947 31130284 15146461 21745757 30606667 23588557 18987351 21856586 31561936 32714263 10714667 23227814 21700212 22006919 24095219 23277556 29029963 34073924 23286447 31216804 33897756 8160756 Number of individuals with the variant: 6 Secondary finding: no
Pathogenic (Jan 21, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Gaucher disease perinatal lethal Affected status: yes Allele origin: germline	Genetics and Molecular Pathology, SA Pathology Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002556469.2 First in ClinVar: Aug 08, 2022 Last updated: Dec 17, 2022	Comment: PS4, PP3, PS3, PP5
Pathogenic (Feb 08, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lewy body dementia Parkinson disease, late-onset Gaucher disease type I Gaucher disease type II Gaucher disease type III Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome Gaucher disease perinatal lethal Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV001652787.2 First in ClinVar: May 29, 2021 Last updated: Dec 31, 2022
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Gaucher disease type III (Autosomal recessive inheritance) Affected status: yes Allele origin: biparental	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India Accession: SCV003935145.1 First in ClinVar: Jul 01, 2023 Last updated: Jul 01, 2023
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Gaucher disease type II (Autosomal recessive inheritance) Affected status: yes Allele origin: maternal	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India Accession: SCV004175898.1 First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023	Sex: female
Pathogenic (May 02, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002024194.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Dec 06, 2022)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV002049503.4 First in ClinVar: Jan 08, 2022 Last updated: Feb 20, 2024	Comment: The GBA c.1448T>C; p.Leu483Pro variant (rs421016), also known as Leu444Pro, is reported in the literature in the homozygous or compound heterozygous state in numerous individuals … (more) The GBA c.1448T>C; p.Leu483Pro variant (rs421016), also known as Leu444Pro, is reported in the literature in the homozygous or compound heterozygous state in numerous individuals affected with Gaucher disease (Grace 1994, Ivanova 2018, Montfort 2004, Saranjam 2013). This variant is found in the general population with an overall allele frequency of 0.12% (345/281386 alleles) in the Genome Aggregation Database. Despite its occurrence in the population, the p.Leu483Pro variant has also been observed to occur de novo in several affected individuals (Saranjam 2013). The leucine at codon 483 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.858). Consistent with predictions, functional studies in both patient-derived cells and cultured cell lines demonstrate enzymatic activity of the variant protein at <10% of normal (Grace 1994, Ivanova 2018, Montfort 2004). Based on available information, the p.Leu483Pro variant is considered to be pathogenic. References: Grace ME et al Analysis of human acid beta-glucosidase by site-directed mutagenesis and heterologous expression. J Biol Chem. 1994 Jan 21;269(3):2283-91. Ivanova MM et al. Individualized screening for chaperone activity in Gaucher disease using multiple patient derived primary cell lines. Am J Transl Res. 2018 Nov 15;10(11):3750-3761. Montfort M et al. Functional analysis of 13 GBA mutant alleles identified in Gaucher disease patients: Pathogenic changes and "modifier" polymorphisms. Hum Mutat. 2004 Jun;23(6):567-75. Saranjam H et al. A germline or de novo mutation in two families with Gaucher disease: implications for recessive disorders. Eur J Hum Genet. 2013 Jan;21(1):115-7. (less)
Pathogenic (Mar 17, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Lewy body dementia Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004805164.2 First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Gaucher disease type I Gaucher disease type II Gaucher disease type III Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome Affected status: unknown Allele origin: germline	Baylor Genetics Accession: SCV001162843.1 First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Gaucher disease Affected status: yes Allele origin: germline	Centogene AG - the Rare Disease Company Accession: SCV001424427.1 First in ClinVar: Jul 27, 2020 Last updated: Jul 27, 2020
Pathogenic (Jul 07, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Gaucher disease type II Affected status: yes Allele origin: unknown	Baylor Genetics Accession: SCV001520375.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Comment: This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Pathogenic (Jan 13, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000491300.1 First in ClinVar: Jan 09, 2017 Last updated: Jan 09, 2017	Comment: Published functional studies demonstrate a damaging effect indicating that this variant is poorly activated by phosphatidylserine, is unstable and has residual enzyme activity of 5-10% … (more) Published functional studies demonstrate a damaging effect indicating that this variant is poorly activated by phosphatidylserine, is unstable and has residual enzyme activity of 5-10% of wild type (Grace et al., 1994; Malini et al., 2014); Identified in the heterozygous state in patients with Lewy body dementia and with Parkinson disease with dementia; however, L483P was also identified in the heterozygous state in control individuals used in these studies (Mata et al., 2008; Nalls et al., 2013); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Previously reported as L444P due to the use of alternate nomenclature; This variant is associated with the following publications: (PMID: 21472771, 21106416, 8294487, 31561936, 23286447, 23227814, 23642305, 21700325, 21700212, 21856586, 22220748, 23635853, 24022302, 22713811, 23783781, 22975760, 20643691, 15146461, 22623374, 23588557, 16293621, 22006919, 25333069, 21742527, 21745757, 22227073, 20131388, 23676350, 24126159, 20004703, 20816920, 18347322, 18987351, 24020503, 25535748, 22160715, 23277556, 22192918, 25249066, 21228398, 8607360, 2880291, 27014572, 18332251, 27094865, 26096741, 27717005, 27153395, 19846850, 27865684, 16967369, 29934114, 11336129, 29625627, 24195576, 29602947, 29140481, 29396846, 28894968, 28003644, 8929950, 10714667, 24095219, 8160756, 30146349, 30548430, 27896091, 29842932, 30537300, 29029963, 29487000, 31193028, 30941926, 30606667, 31216804, 30456712, 31130284, 29471591, 33083013, 32618053, 32883051, 33763395, 33176831, 32658388) (less)
Pathogenic (Nov 26, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Gaucher disease type I Affected status: yes Allele origin: germline	Centogene AG - the Rare Disease Company Accession: SCV002059259.1 First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022
Pathogenic (Jan 22, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Gaucher disease (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV001422763.2 First in ClinVar: Jul 19, 2020 Last updated: Feb 05, 2022	Publications: PubMed (4) PubMed: 17427031‚ 28686011‚ 30662625‚ 23719189 Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/b929ba0d-8dd5-49ad-82bc-61c570246b2f Comment: The p.Leu483Pro variant in GBA has been reported in at least 89 individuals with Gaucher disease (PMID: 17427031, 23719189, 30662625) and has been identified in … (more) The p.Leu483Pro variant in GBA has been reported in at least 89 individuals with Gaucher disease (PMID: 17427031, 23719189, 30662625) and has been identified in 0.245% (25/10202) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs421016). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role and is consistent with the increased prevalence of Gaucher disease in the Ashkenazi Jewish population. This variant has also been reported in ClinVar (VariationID: 4288) as pathogenic by EGL Genetic Diagnostics, Counsyl, GeneDx, Integrated Genetics, Mayo Clinic Genetic Testing Laboratories, Foundation for Research in Genetics and Endocrinology, and OMIM and as likely pathogenic by Praxis fuer Humangenetik Tuebingen. Animal models in mice have shown that this variant causes Gaucher disease (PMID: 28686011). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional likely pathogenic variant, resulting in a different amino acid change at the same position, p.Leu483Arg, has been reported in association with disease in the literature and ClinVar, raising the possibility that a change at this position may not be tolerated (VariationID: 93449; PMID: 27825739). The phenotype of 11 individuals homozygous or compound heterozygous for this variant is highly specific for Gaucher Disease based on beta-glucosidase residual activity <10% of normal, consistent with disease (PMID: 30662625, 23719189). The presence of this variant in 16 affected homozygotes and in combination with reported pathogenic variants (VariationID: 4290, 4293, 4327, 21070, 193611, 4314; PMID: 17427031, 23719189, 30662625) in 67 individuals with Gaucher disease increases the likelihood that the p.Leu483Pro variant is pathogenic. In summary, this variant meets criteria to be classified as pathogenic for Gaucher disease in an autosomal recessive manner based on the presence of the variant in affected individuals and in combination with other pathogenic variants, functional studies, and the phenotype of individuals with this variant being highly specific for Gaucher disease. ACMG/AMP Criteria applied: PM3_very-strong, PS3, PP3, PP4 (Richards 2015). (less)
Pathogenic (Nov 13, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center Accession: SCV002051470.2 First in ClinVar: Jan 08, 2022 Last updated: Feb 05, 2022	Comment: PS3, PP3, PM1, PM2, PM5
Pathogenic (Mar 05, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Gaucher disease Affected status: yes Allele origin: germline	DASA Accession: SCV002107096.2 First in ClinVar: Mar 28, 2022 Last updated: Apr 02, 2022	Publications: PubMed (19) PubMed: 8294487‚ 15146461‚ 30285649‚ 28969384‚ 28727984‚ 28947706‚ 28894968‚ 28546865‚ 20301446‚ 26096741‚ 8929950‚ 22713811‚ 25249066‚ 20816920‚ 27094865‚ 25535748‚ 18987351‚ 23588557‚ 24522292 Comment: Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 8294487; 15146461; 30285649; 28969384) - … (more) Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 8294487; 15146461; 30285649; 28969384) - PS3_moderate.The c.1448T>C;p.(Leu483Pro) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 4288; PMID: 28727984; PMID: 28947706; PMID: 28894968; PMID: 28546865; PMID: 20301446; PMID: 26096741; PMID: 8929950; PMID: 22713811; PMID: 25249066; PMID: 20816920; PMID: 27094865; PMID: 25535748; PMID: 18987351; PMID: 23588557) - PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Glyco_hydro_30C) - PM1. The variant is present at low allele frequencies population databases (rs421016 – gnomAD 0.01226%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Leu483Pro) was detected in trans with a pathogenic variant (PMID: 24522292) - PM3. Pathogenic missense variant in this residue have been reported (Clinvar ID: 93449) - PM5. Missense variant in GBA that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease - PP2. In summary, the currently available evidence indicates that the variant is pathogenic. (less) Number of individuals with the variant: 1 Sex: female Geographic origin: Brazil
Pathogenic (Sep 29, 2020)	criteria provided, single submitter (Classification criteria August 2017) Method: clinical testing	Parkinson disease, late-onset (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München Accession: SCV001150114.2 First in ClinVar: Feb 03, 2020 Last updated: Dec 24, 2022	Observation 1: Number of individuals with the variant: 1 Clinical Features: Dementia (present) , Lewy bodies (present) , Parkinsonian disorder (present) , Hallucinations (present) Observation 2: Number of individuals with the variant: 1 Clinical Features: Parkinsonian disorder (present) Observation 3: Number of individuals with the variant: 1 Clinical Features: Parkinsonian disorder (present) Observation 4: Number of individuals with the variant: 1 Clinical Features: Parkinsonian disorder (present)
Pathogenic (Jan 27, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000964136.5 First in ClinVar: Aug 14, 2019 Last updated: Feb 20, 2024	Publications: PubMed (14) PubMed: 8929950‚ 18987351‚ 20816920‚ 22713811‚ 23588557‚ 23676350‚ 25249066‚ 25535748‚ 26096741‚ 27094865‚ 8294487‚ 15146461‚ 24020503‚ 7981693 Comment: This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 483 of the GBA protein (p.Leu483Pro). … (more) This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 483 of the GBA protein (p.Leu483Pro). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with dementia with Lewy bodies, Gaucher disease, and/or Parkinson's disease (PMID: 8929950, 18987351, 20816920, 22713811, 23588557, 23676350, 25249066, 25535748, 26096741, 27094865). This variant is also known as p.Leu444Pro. ClinVar contains an entry for this variant (Variation ID: 4288). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GBA protein function. Experimental studies have shown that this missense change affects GBA function (PMID: 8294487, 15146461, 24020503). This variant disrupts the p.Leu483 amino acid residue in GBA. Other variant(s) that disrupt this residue have been observed in individuals with GBA-related conditions (PMID: 7981693), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Feb 01, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002755393.2 First in ClinVar: Dec 03, 2022 Last updated: May 01, 2024	Publications: PubMed (6) PubMed: 3353383‚ 10649495‚ 10796875‚ 18338393‚ 24022302‚ 25249066 Comment: The c.1448T>C (p.L483P) alteration is located in exon 11 (coding exon 10) of the GBA gene. This alteration results from a T to C substitution … (more) The c.1448T>C (p.L483P) alteration is located in exon 11 (coding exon 10) of the GBA gene. This alteration results from a T to C substitution at nucleotide position 1448, causing the leucine (L) at amino acid position 483 to be replaced by a proline (P). Based on data from gnomAD, the C allele has an overall frequency of 0.12% (345/281386) total alleles studied. The highest observed frequency was 0.25% (25/10202) of Ashkenazi Jewish alleles. The c.1448T>C (p.L483P) alteration, legacy name p.L444P, is a common pathogenic variant in GBA (Tsuji, 1988; Asselta, 2014; Malini, 2014). Homozygosity is typically associated with Gaucher disease type 3 (subacute, juvenile onset), while heterozygosity for p.L483P with a different GBA pathogenic variant may be associated with Gaucher disease type 2 (acute, infantile onset). The p.L483P mutation appears to be common in affected individuals of Swedish, Japanese, and Ashkenazi Jewish descent (Stone, 2000; Koprivica, 2000; Hruska, 2008). The p.L483 amino acid is conserved in available vertebrate species. Functional analysis of the L483P mutant protein expressed in HEK293 cells revealed that residual GBA activity was 13% as compared to wild-type (Malini, 2014). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. (less)
Pathogenic (Jun 01, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV000800923.3 First in ClinVar: Aug 04, 2018 Last updated: Jun 09, 2024	Publications: Bookshelf: NBK1269 Bookshelf: NBK1269 Number of individuals with the variant: 20
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Gaucher disease type I (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV002073104.2 First in ClinVar: Feb 05, 2022 Last updated: Jul 15, 2024	Comment: The missense c.1448T>C (p.Leu483Pro) variant has been previously reported in homozygous or compound heterozygous state in individuals affected with Gaucher Disease (Grabowski et al, 2015). … (more) The missense c.1448T>C (p.Leu483Pro) variant has been previously reported in homozygous or compound heterozygous state in individuals affected with Gaucher Disease (Grabowski et al, 2015). Experimental studies have shown that this missense change affects GBA function (Migdalska-Richards A, et. al., 2017). This variant is reported with the allele frequency (0.1%) in the gnomAD Exomes and novel in 1000 Genomes. It is submitted to ClinVar with varying interpretations as Likely Pathogenic/ Pathogenic (multiple submissions). The amino acid Leucine at position 483 is changed to a Proline changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted as damaging by SIFT. The residue is conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. (less) Clinical Features: Abnormal metabolism (present)
Pathogenic (Aug 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV000692643.29 First in ClinVar: Jan 09, 2017 Last updated: Oct 20, 2024	Comment: GBA1: PM3:Very Strong, PM5, PS3:Moderate, PM2:Supporting Number of individuals with the variant: 31
Pathogenic (May 06, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Gaucher disease Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002768544.2 First in ClinVar: Dec 24, 2022 Last updated: Nov 24, 2024	Publications: PubMed (4) PubMed: 24022302‚ 26096741‚ 27014572‚ 31010158 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Gaucher disease. (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Intrafamilial variability has been reported (PMID: 31010158). (I) 0200 - Variant is predicted to result in a missense amino acid change from leucine to proline. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2; 345 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (2 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated Glyco_hydro_30C domain (NCBI, PDB, DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed in both homozygotes and compound heterozygotes with Gaucher disease (Clinvar; PMID: 24022302, 27014572, 26096741). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. In vitro assays demonstrated 13% residual enzymatic activity (PMID: 24022302). (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_000157.3(GBA):c.1342G>C; p.(Asp448His)) in a recessive disease. (SP) 1206 - This variant has been shown to be paternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
risk factor (Oct 01, 2013)	no assertion criteria provided Method: literature only	DEMENTIA, LEWY BODY, SUSCEPTIBILITY TO Affected status: not provided Allele origin: germline	OMIM Accession: SCV000024687.7 First in ClinVar: Apr 04, 2013 Last updated: Jun 24, 2017	Publications: PubMed (15) PubMed: 2569551‚ 1899336‚ 22713811‚ 18022370‚ 2880291‚ 2464926‚ 2309702‚ 2378352‚ 1972019‚ 10796875‚ 17620502‚ 18541817‚ 19286695‚ 23448517‚ 18332251 Comment on evidence: The leu444-to-pro (L444P) substitution in exon 10 of the GBA gene has been reported as resulting from a 1448T-C transition (Zimran et al., 1989) and … (more) The leu444-to-pro (L444P) substitution in exon 10 of the GBA gene has been reported as resulting from a 1448T-C transition (Zimran et al., 1989) and from a 6433T-C transition (Latham et al., 1990), depending upon the reference sequence cited. This mutation has alternatively been referred to as LEU483PRO (Saranjam et al., 2013). Reczek et al. (2007) stated that the L444P mutation results in retention of GBA in the ER. They found that overexpression of the human GBA receptor, LIMP2 (SCARB2; 602257), in mouse embryonic fibroblasts rescued lysosomal targeting of GBA with the L444P mutation. Gaucher Disease Tsuji et al. (1987) identified the L444P substitution in the GBA gene in patients with Gaucher disease types I (230800), II (230900), and III (231000). Two of the 5 patients with type II and 7 of the 11 with type III were homozygous for this mutation, whereas 4 of 20 patients with type I Gaucher disease had this mutant allele in heterozygous state. The mutant allele was not found in 29 normal controls. The L444P substitution occurs naturally in the GBA pseudogene. Wigderson et al. (1989) identified the L444P mutation in patients with type I, type II, and type III disease. One patient with type II disease was compound heterozygous for L444P and P415R (606463.0002). Firon et al. (1990) found the L444P mutation in both Ashkenazi Jewish and non-Jewish patients with type I Gaucher disease, but only homozygotes with this mutation had the neurologic forms type II or III. Dahl et al. (1990) found that the Norrbottnian form of Gaucher disease (type III) in Sweden is caused by the L444P mutation. In 3 patients with type I and 1 patient with type II Gaucher disease, Hong et al. (1990) identified a complex allele with 3 point mutations in the GBA gene (606463.0009), 1 of which was L444P. Koprivica et al. (2000) found that homozygosity for L444P was associated with type III Gaucher disease. Saranjam et al. (2013) reported 2 unrelated infants with severe, lethal type II Gaucher disease who were compound heterozygous for 2 mutations in the GBA gene, one of which was L444P. While the other mutation was identified in the paternal line of each patient (see, e.g., T323I, 606463.0017), the L444P allele was not detected in DNA samples from either patient's mother, suggesting that it occurred either as a result of germline mosaicism or as a de novo mutation in 1 ovum that took place during cell division. The findings had implications for genetic counseling, in that even if only 1 parent is found to be a carrier for a recessive disorder, the chance of having an affected child may not be zero. Saranjam et al. (2013) noted that the L444P change occurs at a known mutational hotspot. Parkinson Disease Tan et al. (2007) identified a heterozygous L444P mutation in 8 (2.4%) of 331 Chinese patients with typical Parkinson disease (168600) and none of 347 controls. The age at onset was lower and the percentage of women higher in patients with the L444P mutation compared to those without the mutation. Tan et al. (2007) noted that the findings were significant because Gaucher disease is extremely rare among the Chinese. Gutti et al. (2008) identified the L444P mutation in 4 (2.2%) of 184 Taiwanese patients with PD. Six other GBA variants were identified in 1 patient each, yielding a total of 7 different mutations in 10 patients (5.4%). Gutti et al. (2008) suggested that sequencing the entire GBA gene would reveal additional variant that may contribute to PD. Neumann et al. (2009) identified a heterozygous L444P mutation in 11 (1.39%) of 790 British patients with PD, which was not found in 257 controls. Gonzalez-del Rincon et al. (2013) identified a heterozygous L444P mutation in 7 (5.5%) of 128 Mexican Mestizo patients with early-onset PD (before 45 yeras of age) and in none (0%) of 252 ethnically matched controls. Six (85.7%) of the 7 patients had psychiatric symptoms, including major depressive disorder, generalized anxiety disorder, and obsessive compulsive disorder, which was significantly higher than the prevalence of these disorders in controls (24.7%). In addition, 57% of mutation carriers presented with cognitive decline compared to 5.7% of controls. Gonzalez-del Rincon et al. (2013) concluded that the risk for PD conferred by GBA mutations may be higher than previously thought, and that GBA-associated PD may predispose to psychiatric symptoms. Lewy Body Dementia Mata et al. (2008) identified heterozygosity for the L444P mutation in 10 (1.4%) of 721 PD patients, 1 (1.8%) of 57 patients with Lewy body dementia (DLB; 127750), and 0 of 554 control individuals, all of European origin. Mata et al. (2008) estimated that the population-attributable risk for GBA mutations in Lewy body disorders was only about 3% in patients of European ancestry. (less)
Pathogenic (Oct 01, 2013)	no assertion criteria provided Method: literature only	GAUCHER DISEASE, TYPE I Affected status: not provided Allele origin: germline	OMIM Accession: SCV000024685.7 First in ClinVar: Apr 04, 2013 Last updated: Jun 24, 2017	Publications: PubMed (15) PubMed: 2569551‚ 1899336‚ 22713811‚ 18022370‚ 2880291‚ 2464926‚ 2309702‚ 2378352‚ 1972019‚ 10796875‚ 17620502‚ 18541817‚ 19286695‚ 23448517‚ 18332251 Comment on evidence: The leu444-to-pro (L444P) substitution in exon 10 of the GBA gene has been reported as resulting from a 1448T-C transition (Zimran et al., 1989) and … (more) The leu444-to-pro (L444P) substitution in exon 10 of the GBA gene has been reported as resulting from a 1448T-C transition (Zimran et al., 1989) and from a 6433T-C transition (Latham et al., 1990), depending upon the reference sequence cited. This mutation has alternatively been referred to as LEU483PRO (Saranjam et al., 2013). Reczek et al. (2007) stated that the L444P mutation results in retention of GBA in the ER. They found that overexpression of the human GBA receptor, LIMP2 (SCARB2; 602257), in mouse embryonic fibroblasts rescued lysosomal targeting of GBA with the L444P mutation. Gaucher Disease Tsuji et al. (1987) identified the L444P substitution in the GBA gene in patients with Gaucher disease types I (230800), II (230900), and III (231000). Two of the 5 patients with type II and 7 of the 11 with type III were homozygous for this mutation, whereas 4 of 20 patients with type I Gaucher disease had this mutant allele in heterozygous state. The mutant allele was not found in 29 normal controls. The L444P substitution occurs naturally in the GBA pseudogene. Wigderson et al. (1989) identified the L444P mutation in patients with type I, type II, and type III disease. One patient with type II disease was compound heterozygous for L444P and P415R (606463.0002). Firon et al. (1990) found the L444P mutation in both Ashkenazi Jewish and non-Jewish patients with type I Gaucher disease, but only homozygotes with this mutation had the neurologic forms type II or III. Dahl et al. (1990) found that the Norrbottnian form of Gaucher disease (type III) in Sweden is caused by the L444P mutation. In 3 patients with type I and 1 patient with type II Gaucher disease, Hong et al. (1990) identified a complex allele with 3 point mutations in the GBA gene (606463.0009), 1 of which was L444P. Koprivica et al. (2000) found that homozygosity for L444P was associated with type III Gaucher disease. Saranjam et al. (2013) reported 2 unrelated infants with severe, lethal type II Gaucher disease who were compound heterozygous for 2 mutations in the GBA gene, one of which was L444P. While the other mutation was identified in the paternal line of each patient (see, e.g., T323I, 606463.0017), the L444P allele was not detected in DNA samples from either patient's mother, suggesting that it occurred either as a result of germline mosaicism or as a de novo mutation in 1 ovum that took place during cell division. The findings had implications for genetic counseling, in that even if only 1 parent is found to be a carrier for a recessive disorder, the chance of having an affected child may not be zero. Saranjam et al. (2013) noted that the L444P change occurs at a known mutational hotspot. Parkinson Disease Tan et al. (2007) identified a heterozygous L444P mutation in 8 (2.4%) of 331 Chinese patients with typical Parkinson disease (168600) and none of 347 controls. The age at onset was lower and the percentage of women higher in patients with the L444P mutation compared to those without the mutation. Tan et al. (2007) noted that the findings were significant because Gaucher disease is extremely rare among the Chinese. Gutti et al. (2008) identified the L444P mutation in 4 (2.2%) of 184 Taiwanese patients with PD. Six other GBA variants were identified in 1 patient each, yielding a total of 7 different mutations in 10 patients (5.4%). Gutti et al. (2008) suggested that sequencing the entire GBA gene would reveal additional variant that may contribute to PD. Neumann et al. (2009) identified a heterozygous L444P mutation in 11 (1.39%) of 790 British patients with PD, which was not found in 257 controls. Gonzalez-del Rincon et al. (2013) identified a heterozygous L444P mutation in 7 (5.5%) of 128 Mexican Mestizo patients with early-onset PD (before 45 yeras of age) and in none (0%) of 252 ethnically matched controls. Six (85.7%) of the 7 patients had psychiatric symptoms, including major depressive disorder, generalized anxiety disorder, and obsessive compulsive disorder, which was significantly higher than the prevalence of these disorders in controls (24.7%). In addition, 57% of mutation carriers presented with cognitive decline compared to 5.7% of controls. Gonzalez-del Rincon et al. (2013) concluded that the risk for PD conferred by GBA mutations may be higher than previously thought, and that GBA-associated PD may predispose to psychiatric symptoms. Lewy Body Dementia Mata et al. (2008) identified heterozygosity for the L444P mutation in 10 (1.4%) of 721 PD patients, 1 (1.8%) of 57 patients with Lewy body dementia (DLB; 127750), and 0 of 554 control individuals, all of European origin. Mata et al. (2008) estimated that the population-attributable risk for GBA mutations in Lewy body disorders was only about 3% in patients of European ancestry. (less)
Pathogenic (Oct 01, 2013)	no assertion criteria provided Method: literature only	GAUCHER DISEASE, TYPE II Affected status: not provided Allele origin: germline	OMIM Accession: SCV000024683.7 First in ClinVar: Apr 04, 2013 Last updated: Jun 24, 2017	Publications: PubMed (15) PubMed: 2569551‚ 1899336‚ 22713811‚ 18022370‚ 2880291‚ 2464926‚ 2309702‚ 2378352‚ 1972019‚ 10796875‚ 17620502‚ 18541817‚ 19286695‚ 23448517‚ 18332251 Comment on evidence: The leu444-to-pro (L444P) substitution in exon 10 of the GBA gene has been reported as resulting from a 1448T-C transition (Zimran et al., 1989) and … (more) The leu444-to-pro (L444P) substitution in exon 10 of the GBA gene has been reported as resulting from a 1448T-C transition (Zimran et al., 1989) and from a 6433T-C transition (Latham et al., 1990), depending upon the reference sequence cited. This mutation has alternatively been referred to as LEU483PRO (Saranjam et al., 2013). Reczek et al. (2007) stated that the L444P mutation results in retention of GBA in the ER. They found that overexpression of the human GBA receptor, LIMP2 (SCARB2; 602257), in mouse embryonic fibroblasts rescued lysosomal targeting of GBA with the L444P mutation. Gaucher Disease Tsuji et al. (1987) identified the L444P substitution in the GBA gene in patients with Gaucher disease types I (230800), II (230900), and III (231000). Two of the 5 patients with type II and 7 of the 11 with type III were homozygous for this mutation, whereas 4 of 20 patients with type I Gaucher disease had this mutant allele in heterozygous state. The mutant allele was not found in 29 normal controls. The L444P substitution occurs naturally in the GBA pseudogene. Wigderson et al. (1989) identified the L444P mutation in patients with type I, type II, and type III disease. One patient with type II disease was compound heterozygous for L444P and P415R (606463.0002). Firon et al. (1990) found the L444P mutation in both Ashkenazi Jewish and non-Jewish patients with type I Gaucher disease, but only homozygotes with this mutation had the neurologic forms type II or III. Dahl et al. (1990) found that the Norrbottnian form of Gaucher disease (type III) in Sweden is caused by the L444P mutation. In 3 patients with type I and 1 patient with type II Gaucher disease, Hong et al. (1990) identified a complex allele with 3 point mutations in the GBA gene (606463.0009), 1 of which was L444P. Koprivica et al. (2000) found that homozygosity for L444P was associated with type III Gaucher disease. Saranjam et al. (2013) reported 2 unrelated infants with severe, lethal type II Gaucher disease who were compound heterozygous for 2 mutations in the GBA gene, one of which was L444P. While the other mutation was identified in the paternal line of each patient (see, e.g., T323I, 606463.0017), the L444P allele was not detected in DNA samples from either patient's mother, suggesting that it occurred either as a result of germline mosaicism or as a de novo mutation in 1 ovum that took place during cell division. The findings had implications for genetic counseling, in that even if only 1 parent is found to be a carrier for a recessive disorder, the chance of having an affected child may not be zero. Saranjam et al. (2013) noted that the L444P change occurs at a known mutational hotspot. Parkinson Disease Tan et al. (2007) identified a heterozygous L444P mutation in 8 (2.4%) of 331 Chinese patients with typical Parkinson disease (168600) and none of 347 controls. The age at onset was lower and the percentage of women higher in patients with the L444P mutation compared to those without the mutation. Tan et al. (2007) noted that the findings were significant because Gaucher disease is extremely rare among the Chinese. Gutti et al. (2008) identified the L444P mutation in 4 (2.2%) of 184 Taiwanese patients with PD. Six other GBA variants were identified in 1 patient each, yielding a total of 7 different mutations in 10 patients (5.4%). Gutti et al. (2008) suggested that sequencing the entire GBA gene would reveal additional variant that may contribute to PD. Neumann et al. (2009) identified a heterozygous L444P mutation in 11 (1.39%) of 790 British patients with PD, which was not found in 257 controls. Gonzalez-del Rincon et al. (2013) identified a heterozygous L444P mutation in 7 (5.5%) of 128 Mexican Mestizo patients with early-onset PD (before 45 yeras of age) and in none (0%) of 252 ethnically matched controls. Six (85.7%) of the 7 patients had psychiatric symptoms, including major depressive disorder, generalized anxiety disorder, and obsessive compulsive disorder, which was significantly higher than the prevalence of these disorders in controls (24.7%). In addition, 57% of mutation carriers presented with cognitive decline compared to 5.7% of controls. Gonzalez-del Rincon et al. (2013) concluded that the risk for PD conferred by GBA mutations may be higher than previously thought, and that GBA-associated PD may predispose to psychiatric symptoms. Lewy Body Dementia Mata et al. (2008) identified heterozygosity for the L444P mutation in 10 (1.4%) of 721 PD patients, 1 (1.8%) of 57 patients with Lewy body dementia (DLB; 127750), and 0 of 554 control individuals, all of European origin. Mata et al. (2008) estimated that the population-attributable risk for GBA mutations in Lewy body disorders was only about 3% in patients of European ancestry. (less)
Pathogenic (Oct 01, 2013)	no assertion criteria provided Method: literature only	GAUCHER DISEASE, TYPE III Affected status: not provided Allele origin: germline	OMIM Accession: SCV000024684.7 First in ClinVar: Apr 04, 2013 Last updated: Jun 24, 2017	Publications: PubMed (15) PubMed: 2569551‚ 1899336‚ 22713811‚ 18022370‚ 2880291‚ 2464926‚ 2309702‚ 2378352‚ 1972019‚ 10796875‚ 17620502‚ 18541817‚ 19286695‚ 23448517‚ 18332251 Comment on evidence: The leu444-to-pro (L444P) substitution in exon 10 of the GBA gene has been reported as resulting from a 1448T-C transition (Zimran et al., 1989) and … (more) The leu444-to-pro (L444P) substitution in exon 10 of the GBA gene has been reported as resulting from a 1448T-C transition (Zimran et al., 1989) and from a 6433T-C transition (Latham et al., 1990), depending upon the reference sequence cited. This mutation has alternatively been referred to as LEU483PRO (Saranjam et al., 2013). Reczek et al. (2007) stated that the L444P mutation results in retention of GBA in the ER. They found that overexpression of the human GBA receptor, LIMP2 (SCARB2; 602257), in mouse embryonic fibroblasts rescued lysosomal targeting of GBA with the L444P mutation. Gaucher Disease Tsuji et al. (1987) identified the L444P substitution in the GBA gene in patients with Gaucher disease types I (230800), II (230900), and III (231000). Two of the 5 patients with type II and 7 of the 11 with type III were homozygous for this mutation, whereas 4 of 20 patients with type I Gaucher disease had this mutant allele in heterozygous state. The mutant allele was not found in 29 normal controls. The L444P substitution occurs naturally in the GBA pseudogene. Wigderson et al. (1989) identified the L444P mutation in patients with type I, type II, and type III disease. One patient with type II disease was compound heterozygous for L444P and P415R (606463.0002). Firon et al. (1990) found the L444P mutation in both Ashkenazi Jewish and non-Jewish patients with type I Gaucher disease, but only homozygotes with this mutation had the neurologic forms type II or III. Dahl et al. (1990) found that the Norrbottnian form of Gaucher disease (type III) in Sweden is caused by the L444P mutation. In 3 patients with type I and 1 patient with type II Gaucher disease, Hong et al. (1990) identified a complex allele with 3 point mutations in the GBA gene (606463.0009), 1 of which was L444P. Koprivica et al. (2000) found that homozygosity for L444P was associated with type III Gaucher disease. Saranjam et al. (2013) reported 2 unrelated infants with severe, lethal type II Gaucher disease who were compound heterozygous for 2 mutations in the GBA gene, one of which was L444P. While the other mutation was identified in the paternal line of each patient (see, e.g., T323I, 606463.0017), the L444P allele was not detected in DNA samples from either patient's mother, suggesting that it occurred either as a result of germline mosaicism or as a de novo mutation in 1 ovum that took place during cell division. The findings had implications for genetic counseling, in that even if only 1 parent is found to be a carrier for a recessive disorder, the chance of having an affected child may not be zero. Saranjam et al. (2013) noted that the L444P change occurs at a known mutational hotspot. Parkinson Disease Tan et al. (2007) identified a heterozygous L444P mutation in 8 (2.4%) of 331 Chinese patients with typical Parkinson disease (168600) and none of 347 controls. The age at onset was lower and the percentage of women higher in patients with the L444P mutation compared to those without the mutation. Tan et al. (2007) noted that the findings were significant because Gaucher disease is extremely rare among the Chinese. Gutti et al. (2008) identified the L444P mutation in 4 (2.2%) of 184 Taiwanese patients with PD. Six other GBA variants were identified in 1 patient each, yielding a total of 7 different mutations in 10 patients (5.4%). Gutti et al. (2008) suggested that sequencing the entire GBA gene would reveal additional variant that may contribute to PD. Neumann et al. (2009) identified a heterozygous L444P mutation in 11 (1.39%) of 790 British patients with PD, which was not found in 257 controls. Gonzalez-del Rincon et al. (2013) identified a heterozygous L444P mutation in 7 (5.5%) of 128 Mexican Mestizo patients with early-onset PD (before 45 yeras of age) and in none (0%) of 252 ethnically matched controls. Six (85.7%) of the 7 patients had psychiatric symptoms, including major depressive disorder, generalized anxiety disorder, and obsessive compulsive disorder, which was significantly higher than the prevalence of these disorders in controls (24.7%). In addition, 57% of mutation carriers presented with cognitive decline compared to 5.7% of controls. Gonzalez-del Rincon et al. (2013) concluded that the risk for PD conferred by GBA mutations may be higher than previously thought, and that GBA-associated PD may predispose to psychiatric symptoms. Lewy Body Dementia Mata et al. (2008) identified heterozygosity for the L444P mutation in 10 (1.4%) of 721 PD patients, 1 (1.8%) of 57 patients with Lewy body dementia (DLB; 127750), and 0 of 554 control individuals, all of European origin. Mata et al. (2008) estimated that the population-attributable risk for GBA mutations in Lewy body disorders was only about 3% in patients of European ancestry. (less)
Likely pathogenic (Jun 29, 2018)	no assertion criteria provided Method: clinical testing	Gaucher disease type II (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics Accession: SCV000786647.1 First in ClinVar: Jun 24, 2017 Last updated: Jun 24, 2017	Comment: The observed variant c.1448T>C (p.Leu483Pro) has a minor allele frequency of 0.0034 in 1000 Genomes and 0.003099 in ExAC databases. The in silico prediction of … (more) The observed variant c.1448T>C (p.Leu483Pro) has a minor allele frequency of 0.0034 in 1000 Genomes and 0.003099 in ExAC databases. The in silico prediction of the given variant is disease causing by MutationTaster2, damaging by SIFT and possibly damaging by PolyPhen2. This variant was detected as a compound heterozygous along with another variant c.1448T>G (p.Leu483Arg). The variant c.1448T>G (p.Leu483Arg) was neither found in 1000 Genomes and ExAC databases. The in silico prediction of the given variant is disease causing by MutationTaster2, damaging by SIFT and probably damaging by PolyPhen2. (less) Clinical Features: Motor delay (present) , Esotropia (present) , Hepatosplenomegaly (present) Age: 0-9 years Sex: male Ethnicity/Population group: Hindu Geographic origin: India Method: The exon and the exon-intron boundaries of the GBA gene were bidirectionally sequenced using an automated sequencer.
Pathogenic (Jan 03, 2019)	no assertion criteria provided Method: clinical testing	Gaucher disease type I (Autosomal recessive inheritance) Affected status: no Allele origin: germline	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics Accession: SCV000864168.1 First in ClinVar: Jan 22, 2019 Last updated: Jan 22, 2019	Comment: The variant NM_000157.4: c.1448T>C(p.L483P) in exon-10 of GBA gene has been seen in heterozygous status. It is the most common mutation in Indian patients affected … (more) The variant NM_000157.4: c.1448T>C(p.L483P) in exon-10 of GBA gene has been seen in heterozygous status. It is the most common mutation in Indian patients affected with Gaucher's Disease. (less) Indication for testing: Previous siblings are affected with Gaucher diseases with known compound heterozygous mutation L444P/D380H Age: 0-9 years Sex: female Ethnicity/Population group: Indian Hindu Geographic origin: India Method: DNA was used to perform PCR bi-directional Sanger sequencing. Sequence obtained was aligned to a reference gene using BLAST tool and then analyzed using Chromas to identify variants in the targeted gene relevant to the clinical indication.
Pathogenic (Mar 17, 2017)	no assertion criteria provided Method: clinical testing	Gaucher disease Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002086449.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022
risk factor (Oct 01, 2013)	no assertion criteria provided Method: literature only	PARKINSON DISEASE, LATE-ONSET, SUSCEPTIBILITY TO Affected status: not provided Allele origin: germline	OMIM Accession: SCV002540612.1 First in ClinVar: Jul 09, 2022 Last updated: Jul 09, 2022	Publications: PubMed (15) PubMed: 2569551‚ 1899336‚ 22713811‚ 18022370‚ 2880291‚ 2464926‚ 2309702‚ 2378352‚ 1972019‚ 10796875‚ 17620502‚ 18541817‚ 19286695‚ 23448517‚ 18332251 Comment on evidence: The leu444-to-pro (L444P) substitution in exon 10 of the GBA gene has been reported as resulting from a 1448T-C transition (Zimran et al., 1989) and … (more) The leu444-to-pro (L444P) substitution in exon 10 of the GBA gene has been reported as resulting from a 1448T-C transition (Zimran et al., 1989) and from a 6433T-C transition (Latham et al., 1990), depending upon the reference sequence cited. This mutation has alternatively been referred to as LEU483PRO (Saranjam et al., 2013). Reczek et al. (2007) stated that the L444P mutation results in retention of GBA in the ER. They found that overexpression of the human GBA receptor, LIMP2 (SCARB2; 602257), in mouse embryonic fibroblasts rescued lysosomal targeting of GBA with the L444P mutation. Gaucher Disease Tsuji et al. (1987) identified the L444P substitution in the GBA gene in patients with Gaucher disease types I (230800), II (230900), and III (231000). Two of the 5 patients with type II and 7 of the 11 with type III were homozygous for this mutation, whereas 4 of 20 patients with type I Gaucher disease had this mutant allele in heterozygous state. The mutant allele was not found in 29 normal controls. The L444P substitution occurs naturally in the GBA pseudogene. Wigderson et al. (1989) identified the L444P mutation in patients with type I, type II, and type III disease. One patient with type II disease was compound heterozygous for L444P and P415R (606463.0002). Firon et al. (1990) found the L444P mutation in both Ashkenazi Jewish and non-Jewish patients with type I Gaucher disease, but only homozygotes with this mutation had the neurologic forms type II or III. Dahl et al. (1990) found that the Norrbottnian form of Gaucher disease (type III) in Sweden is caused by the L444P mutation. In 3 patients with type I and 1 patient with type II Gaucher disease, Hong et al. (1990) identified a complex allele with 3 point mutations in the GBA gene (606463.0009), 1 of which was L444P. Koprivica et al. (2000) found that homozygosity for L444P was associated with type III Gaucher disease. Saranjam et al. (2013) reported 2 unrelated infants with severe, lethal type II Gaucher disease who were compound heterozygous for 2 mutations in the GBA gene, one of which was L444P. While the other mutation was identified in the paternal line of each patient (see, e.g., T323I, 606463.0017), the L444P allele was not detected in DNA samples from either patient's mother, suggesting that it occurred either as a result of germline mosaicism or as a de novo mutation in 1 ovum that took place during cell division. The findings had implications for genetic counseling, in that even if only 1 parent is found to be a carrier for a recessive disorder, the chance of having an affected child may not be zero. Saranjam et al. (2013) noted that the L444P change occurs at a known mutational hotspot. Parkinson Disease Tan et al. (2007) identified a heterozygous L444P mutation in 8 (2.4%) of 331 Chinese patients with typical Parkinson disease (168600) and none of 347 controls. The age at onset was lower and the percentage of women higher in patients with the L444P mutation compared to those without the mutation. Tan et al. (2007) noted that the findings were significant because Gaucher disease is extremely rare among the Chinese. Gutti et al. (2008) identified the L444P mutation in 4 (2.2%) of 184 Taiwanese patients with PD. Six other GBA variants were identified in 1 patient each, yielding a total of 7 different mutations in 10 patients (5.4%). Gutti et al. (2008) suggested that sequencing the entire GBA gene would reveal additional variant that may contribute to PD. Neumann et al. (2009) identified a heterozygous L444P mutation in 11 (1.39%) of 790 British patients with PD, which was not found in 257 controls. Gonzalez-del Rincon et al. (2013) identified a heterozygous L444P mutation in 7 (5.5%) of 128 Mexican Mestizo patients with early-onset PD (before 45 yeras of age) and in none (0%) of 252 ethnically matched controls. Six (85.7%) of the 7 patients had psychiatric symptoms, including major depressive disorder, generalized anxiety disorder, and obsessive compulsive disorder, which was significantly higher than the prevalence of these disorders in controls (24.7%). In addition, 57% of mutation carriers presented with cognitive decline compared to 5.7% of controls. Gonzalez-del Rincon et al. (2013) concluded that the risk for PD conferred by GBA mutations may be higher than previously thought, and that GBA-associated PD may predispose to psychiatric symptoms. Lewy Body Dementia Mata et al. (2008) identified heterozygosity for the L444P mutation in 10 (1.4%) of 721 PD patients, 1 (1.8%) of 57 patients with Lewy body dementia (DLB; 127750), and 0 of 554 control individuals, all of European origin. Mata et al. (2008) estimated that the population-attributable risk for GBA mutations in Lewy body disorders was only about 3% in patients of European ancestry. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	Gaucher disease type I (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Dr.Nikuei Genetic Center Accession: SCV005061393.1 First in ClinVar: Jun 23, 2024 Last updated: Jun 23, 2024
Pathogenic (Aug 29, 2024)	no assertion criteria provided Method: clinical testing	GBA1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004120381.3 First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024	Comment: The GBA1 c.1448T>C variant is predicted to result in the amino acid substitution p.Leu483Pro. This variant is the second most prevalent variant in Gaucher disease … (more) The GBA1 c.1448T>C variant is predicted to result in the amino acid substitution p.Leu483Pro. This variant is the second most prevalent variant in Gaucher disease (Alfonso et al. 2007. PubMed ID: 17427031) and the most common GBA mutation leading to the Type 3 (GD3) of Gaucher disease (Ivanova et al. 2018. PubMed ID: 30662625). This variant was observed in homozygous and compound heterozygous state in multiple individuals with Gaucher disease (Tsuji et al. 1987. PubMed ID: 2880291; Grabowski et al, 2015 PubMed ID: 26096741; Alfonso et al. 2007. PubMed ID: 17427031; Tammachote et al. 2013. PubMed ID: 23719189; Ivanova et al. 2018. PubMed ID: 30662625) and in heterozygous state in individuals with Parkinson disease or dementia with Lewy bodies (Nichols 2009 PubMed ID: 18987351; Santos 2010 PubMed ID: PMID: 20816920; Nalls et al. 2013. PubMed ID: 23588557). Beta-glucosidase residual activity in individuals homozygous and compound heterozygous for this variant is reported below <10% of normal, consistent with Gaucher disease (Ivanova et al. 2018. PubMed ID: 30662625; Tammachote et al. 2013. PubMed ID: 23719189). This variant is reported in 0.25% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is interpreted as pathogenic for Gaucher disease, but a risk factor for Parkinson disease. XXXXXXXXXXXXXXXXXXXXX This variant can be also a part of pathogenic recombinant alleles RecNciI c.[1448T>C;1483G>C;1497G>C] or RecTL c.[1342G>C;1448T>C;1483G>C;1497G>C] . If other variants are also present in the patient, use RecNciI or RecTL variant interpretation text in Variant notes XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX (less)
Pathogenic (Apr 01, 2023)	no assertion criteria provided Method: clinical testing	Gaucher disease type III Affected status: yes Allele origin: germline	Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS) Accession: SCV003927798.1 First in ClinVar: Sep 16, 2023 Last updated: Sep 16, 2023
Pathogenic (-)	no assertion criteria provided Method: literature only	Gaucher disease type I (Autosomal recessive inheritance) Affected status: unknown Allele origin: biparental	Department of Traditional Chinese Medicine, Fujian Provincial Hospital Accession: SCV004100811.1 First in ClinVar: Nov 11, 2023 Last updated: Nov 11, 2023	Publications: DOI: 10.1056/NEJM198703053161002 DOI: 10.1056/NEJM198703053161002 DOI: 10.1002/jmd2.12201 DOI: 10.1002/jmd2.12201 Comment: A patient with combined splenomegaly and thrombocytopenia was genetically tested for mutant GBA (NM_001005741): c.1448T>C (p.Leu483Pro), which is a missense mutation in exon 11, for … (more) A patient with combined splenomegaly and thrombocytopenia was genetically tested for mutant GBA (NM_001005741): c.1448T>C (p.Leu483Pro), which is a missense mutation in exon 11, for which damage to protein function is predicted by:SIFT: Deleterious; Polyphen2: Possibly damaging; MutationTaster: disease causing automatic. According to the ACMG guidelines, this mutation site meets: PS3: Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product; PM1: Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation; PM3: For recessive disorders, detected in trans with a pathogenic variant; and PP3: Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc). This mutation has been reported to cause "Gaucher disease"( PMID: 2880291) and is therefore considered "Pathogenic". (less)
not provided (-)	no classification provided Method: literature only	Gaucher disease Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV000040477.3 First in ClinVar: Apr 04, 2013 Last updated: Oct 29, 2022	Publications: Bookshelf: NBK1269 Bookshelf: NBK1269
not provided (-)	no classification provided Method: phenotyping only	Gaucher disease perinatal lethal Gaucher disease perinatal lethal Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: de novo	GenomeConnect - Brain Gene Registry Accession: SCV004804542.1 First in ClinVar: Mar 30, 2024 Last updated: Mar 30, 2024	Comment: Variant classified as Pathogenic and reported on 12-06-2012 by Baylor College of Medicine. Assertions are reported exactly as they appear on the patient provided laboratory … (more) Variant classified as Pathogenic and reported on 12-06-2012 by Baylor College of Medicine. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. (less) Clinical Features: Global developmental delay (present) , Hypotonia (present) , Delayed speech and language development (present) Indication for testing: Diagnostic Age: 0-9 years Sex: male Method: Exome Sequencing Testing laboratory: Baylor Genetics Date variant was reported to submitter: 2012-12-06 Testing laboratory interpretation: Pathogenic
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Comment:

NM_001005741.2(GBA):c.1448T>C(L483P, aka L444P) is classified as pathogenic in the context of Gaucher disease. The L483P variant can be associated with either Type 1, 2 or 3 Gaucher disease. Sources cited for classification include the following: PMID 2880291, 15146461, 21106416, 27123474 and 9375849. Classification of NM_001005741.2(GBA):c.1448T>C(L483P, aka L444P) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

Comment:

Variant summary: GBA c.1448T>C (p.Leu483Pro) results in a non-conservative amino acid change located in the Glycosyl hydrolase family 30, beta sandwich domain (IPR033452) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0013 in 250058 control chromosomes (gnomAD). c.1448T>C has been reported in the literature in multiple individuals affected with Gaucher Disease (Miocic_ 2005, Malini_2013, Siebert_2013, Tammachote_2013). These data indicate that the variant is very likely to be associated with disease. Functional studies report the variant effect results in decreasing GBA enzyme activity in transfected cells (Alfonso__2004, Malini_2013). 12 ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=11) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000004288, PS1_S).Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 28969384, 15146461, PS3_S). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000093449, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.858, 3CNET: 0.995, PP3_P). A missense variant is a common mechanism associated with Parkinson disease (PP2_P). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

The GBA c.1448T>C; p.Leu483Pro variant (rs421016), also known as Leu444Pro, is reported in the literature in the homozygous or compound heterozygous state in numerous individuals affected with Gaucher disease (Grace 1994, Ivanova 2018, Montfort 2004, Saranjam 2013). This variant is found in the general population with an overall allele frequency of 0.12% (345/281386 alleles) in the Genome Aggregation Database. Despite its occurrence in the population, the p.Leu483Pro variant has also been observed to occur de novo in several affected individuals (Saranjam 2013). The leucine at codon 483 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.858). Consistent with predictions, functional studies in both patient-derived cells and cultured cell lines demonstrate enzymatic activity of the variant protein at <10% of normal (Grace 1994, Ivanova 2018, Montfort 2004). Based on available information, the p.Leu483Pro variant is considered to be pathogenic. References: Grace ME et al Analysis of human acid beta-glucosidase by site-directed mutagenesis and heterologous expression. J Biol Chem. 1994 Jan 21;269(3):2283-91. Ivanova MM et al. Individualized screening for chaperone activity in Gaucher disease using multiple patient derived primary cell lines. Am J Transl Res. 2018 Nov 15;10(11):3750-3761. Montfort M et al. Functional analysis of 13 GBA mutant alleles identified in Gaucher disease patients: Pathogenic changes and "modifier" polymorphisms. Hum Mutat. 2004 Jun;23(6):567-75. Saranjam H et al. A germline or de novo mutation in two families with Gaucher disease: implications for recessive disorders. Eur J Hum Genet. 2013 Jan;21(1):115-7.

Comment:

Published functional studies demonstrate a damaging effect indicating that this variant is poorly activated by phosphatidylserine, is unstable and has residual enzyme activity of 5-10% of wild type (Grace et al., 1994; Malini et al., 2014); Identified in the heterozygous state in patients with Lewy body dementia and with Parkinson disease with dementia; however, L483P was also identified in the heterozygous state in control individuals used in these studies (Mata et al., 2008; Nalls et al., 2013); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Previously reported as L444P due to the use of alternate nomenclature; This variant is associated with the following publications: (PMID: 21472771, 21106416, 8294487, 31561936, 23286447, 23227814, 23642305, 21700325, 21700212, 21856586, 22220748, 23635853, 24022302, 22713811, 23783781, 22975760, 20643691, 15146461, 22623374, 23588557, 16293621, 22006919, 25333069, 21742527, 21745757, 22227073, 20131388, 23676350, 24126159, 20004703, 20816920, 18347322, 18987351, 24020503, 25535748, 22160715, 23277556, 22192918, 25249066, 21228398, 8607360, 2880291, 27014572, 18332251, 27094865, 26096741, 27717005, 27153395, 19846850, 27865684, 16967369, 29934114, 11336129, 29625627, 24195576, 29602947, 29140481, 29396846, 28894968, 28003644, 8929950, 10714667, 24095219, 8160756, 30146349, 30548430, 27896091, 29842932, 30537300, 29029963, 29487000, 31193028, 30941926, 30606667, 31216804, 30456712, 31130284, 29471591, 33083013, 32618053, 32883051, 33763395, 33176831, 32658388)

Comment:

The p.Leu483Pro variant in GBA has been reported in at least 89 individuals with Gaucher disease (PMID: 17427031, 23719189, 30662625) and has been identified in 0.245% (25/10202) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs421016). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role and is consistent with the increased prevalence of Gaucher disease in the Ashkenazi Jewish population. This variant has also been reported in ClinVar (VariationID: 4288) as pathogenic by EGL Genetic Diagnostics, Counsyl, GeneDx, Integrated Genetics, Mayo Clinic Genetic Testing Laboratories, Foundation for Research in Genetics and Endocrinology, and OMIM and as likely pathogenic by Praxis fuer Humangenetik Tuebingen. Animal models in mice have shown that this variant causes Gaucher disease (PMID: 28686011). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional likely pathogenic variant, resulting in a different amino acid change at the same position, p.Leu483Arg, has been reported in association with disease in the literature and ClinVar, raising the possibility that a change at this position may not be tolerated (VariationID: 93449; PMID: 27825739). The phenotype of 11 individuals homozygous or compound heterozygous for this variant is highly specific for Gaucher Disease based on beta-glucosidase residual activity <10% of normal, consistent with disease (PMID: 30662625, 23719189). The presence of this variant in 16 affected homozygotes and in combination with reported pathogenic variants (VariationID: 4290, 4293, 4327, 21070, 193611, 4314; PMID: 17427031, 23719189, 30662625) in 67 individuals with Gaucher disease increases the likelihood that the p.Leu483Pro variant is pathogenic. In summary, this variant meets criteria to be classified as pathogenic for Gaucher disease in an autosomal recessive manner based on the presence of the variant in affected individuals and in combination with other pathogenic variants, functional studies, and the phenotype of individuals with this variant being highly specific for Gaucher disease. ACMG/AMP Criteria applied: PM3_very-strong, PS3, PP3, PP4 (Richards 2015).

Comment:

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 8294487; 15146461; 30285649; 28969384) - PS3_moderate.The c.1448T>C;p.(Leu483Pro) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 4288; PMID: 28727984; PMID: 28947706; PMID: 28894968; PMID: 28546865; PMID: 20301446; PMID: 26096741; PMID: 8929950; PMID: 22713811; PMID: 25249066; PMID: 20816920; PMID: 27094865; PMID: 25535748; PMID: 18987351; PMID: 23588557) - PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Glyco_hydro_30C) - PM1. The variant is present at low allele frequencies population databases (rs421016 – gnomAD 0.01226%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Leu483Pro) was detected in trans with a pathogenic variant (PMID: 24522292) - PM3. Pathogenic missense variant in this residue have been reported (Clinvar ID: 93449) - PM5. Missense variant in GBA that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease - PP2. In summary, the currently available evidence indicates that the variant is pathogenic.

Comment:

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 483 of the GBA protein (p.Leu483Pro). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with dementia with Lewy bodies, Gaucher disease, and/or Parkinson's disease (PMID: 8929950, 18987351, 20816920, 22713811, 23588557, 23676350, 25249066, 25535748, 26096741, 27094865). This variant is also known as p.Leu444Pro. ClinVar contains an entry for this variant (Variation ID: 4288). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GBA protein function. Experimental studies have shown that this missense change affects GBA function (PMID: 8294487, 15146461, 24020503). This variant disrupts the p.Leu483 amino acid residue in GBA. Other variant(s) that disrupt this residue have been observed in individuals with GBA-related conditions (PMID: 7981693), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

Comment:

The c.1448T>C (p.L483P) alteration is located in exon 11 (coding exon 10) of the GBA gene. This alteration results from a T to C substitution at nucleotide position 1448, causing the leucine (L) at amino acid position 483 to be replaced by a proline (P). Based on data from gnomAD, the C allele has an overall frequency of 0.12% (345/281386) total alleles studied. The highest observed frequency was 0.25% (25/10202) of Ashkenazi Jewish alleles. The c.1448T>C (p.L483P) alteration, legacy name p.L444P, is a common pathogenic variant in GBA (Tsuji, 1988; Asselta, 2014; Malini, 2014). Homozygosity is typically associated with Gaucher disease type 3 (subacute, juvenile onset), while heterozygosity for p.L483P with a different GBA pathogenic variant may be associated with Gaucher disease type 2 (acute, infantile onset). The p.L483P mutation appears to be common in affected individuals of Swedish, Japanese, and Ashkenazi Jewish descent (Stone, 2000; Koprivica, 2000; Hruska, 2008). The p.L483 amino acid is conserved in available vertebrate species. Functional analysis of the L483P mutant protein expressed in HEK293 cells revealed that residual GBA activity was 13% as compared to wild-type (Malini, 2014). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

Comment:

The missense c.1448T>C (p.Leu483Pro) variant has been previously reported in homozygous or compound heterozygous state in individuals affected with Gaucher Disease (Grabowski et al, 2015). Experimental studies have shown that this missense change affects GBA function (Migdalska-Richards A, et. al., 2017). This variant is reported with the allele frequency (0.1%) in the gnomAD Exomes and novel in 1000 Genomes. It is submitted to ClinVar with varying interpretations as Likely Pathogenic/ Pathogenic (multiple submissions). The amino acid Leucine at position 483 is changed to a Proline changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted as damaging by SIFT. The residue is conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Gaucher disease. (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Intrafamilial variability has been reported (PMID: 31010158). (I) 0200 - Variant is predicted to result in a missense amino acid change from leucine to proline. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2; 345 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (2 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated Glyco_hydro_30C domain (NCBI, PDB, DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed in both homozygotes and compound heterozygotes with Gaucher disease (Clinvar; PMID: 24022302, 27014572, 26096741). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. In vitro assays demonstrated 13% residual enzymatic activity (PMID: 24022302). (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_000157.3(GBA):c.1342G>C; p.(Asp448His)) in a recessive disease. (SP) 1206 - This variant has been shown to be paternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Comment:

The observed variant c.1448T>C (p.Leu483Pro) has a minor allele frequency of 0.0034 in 1000 Genomes and 0.003099 in ExAC databases. The in silico prediction of the given variant is disease causing by MutationTaster2, damaging by SIFT and possibly damaging by PolyPhen2. This variant was detected as a compound heterozygous along with another variant c.1448T>G (p.Leu483Arg). The variant c.1448T>G (p.Leu483Arg) was neither found in 1000 Genomes and ExAC databases. The in silico prediction of the given variant is disease causing by MutationTaster2, damaging by SIFT and probably damaging by PolyPhen2.

Comment:

The GBA1 c.1448T>C variant is predicted to result in the amino acid substitution p.Leu483Pro. This variant is the second most prevalent variant in Gaucher disease (Alfonso et al. 2007. PubMed ID: 17427031) and the most common GBA mutation leading to the Type 3 (GD3) of Gaucher disease (Ivanova et al. 2018. PubMed ID: 30662625). This variant was observed in homozygous and compound heterozygous state in multiple individuals with Gaucher disease (Tsuji et al. 1987. PubMed ID: 2880291; Grabowski et al, 2015 PubMed ID: 26096741; Alfonso et al. 2007. PubMed ID: 17427031; Tammachote et al. 2013. PubMed ID: 23719189; Ivanova et al. 2018. PubMed ID: 30662625) and in heterozygous state in individuals with Parkinson disease or dementia with Lewy bodies (Nichols 2009 PubMed ID: 18987351; Santos 2010 PubMed ID: PMID: 20816920; Nalls et al. 2013. PubMed ID: 23588557). Beta-glucosidase residual activity in individuals homozygous and compound heterozygous for this variant is reported below <10% of normal, consistent with Gaucher disease (Ivanova et al. 2018. PubMed ID: 30662625; Tammachote et al. 2013. PubMed ID: 23719189). This variant is reported in 0.25% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is interpreted as pathogenic for Gaucher disease, but a risk factor for Parkinson disease. XXXXXXXXXXXXXXXXXXXXX This variant can be also a part of pathogenic recombinant alleles RecNciI c.[1448T>C;1483G>C;1497G>C] or RecTL c.[1342G>C;1448T>C;1483G>C;1497G>C] . If other variants are also present in the patient, use RecNciI or RecTL variant interpretation text in Variant notes XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX

Comment:

A patient with combined splenomegaly and thrombocytopenia was genetically tested for mutant GBA (NM_001005741): c.1448T>C (p.Leu483Pro), which is a missense mutation in exon 11, for which damage to protein function is predicted by:SIFT: Deleterious; Polyphen2: Possibly damaging; MutationTaster: disease causing automatic. According to the ACMG guidelines, this mutation site meets: PS3: Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product; PM1: Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation; PM3: For recessive disorders, detected in trans with a pathogenic variant; and PP3: Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc). This mutation has been reported to cause "Gaucher disease"( PMID: 2880291) and is therefore considered "Pathogenic".

Comment:

Variant classified as Pathogenic and reported on 12-06-2012 by Baylor College of Medicine. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Gaucher Disease.	Adam MP	-	2023	PMID: 20301446
Cardiopulmonary assessment of patients diagnosed with Gaucher's disease type I.	Bjelobrk M	Molecular genetics & genomic medicine	2021	PMID: 34275192
Accurate Molecular Diagnosis of Gaucher Disease Using Clinical Exome Sequencing as a First-Tier Test.	Zampieri S	International journal of molecular sciences	2021	PMID: 34073924
Selective screening for lysosomal storage disorders in a large cohort of minorities of African descent shows high prevalence rates and novel variants.	Limgala RP	JIMD reports	2021	DOI: 10.1002/jmd2.12201
Selective screening for lysosomal storage disorders in a large cohort of minorities of African descent shows high prevalence rates and novel variants.	Limgala RP	JIMD reports	2021	PMID: 33977031
Value of Exome Sequencing in Diagnosis and Management of Recurrent Non-immune Hydrops Fetalis: A Retrospective Analysis.	Zhou X	Frontiers in genetics	2021	PMID: 33897756
Clinical and Genetic Spectra of Inherited Liver Disease in Children in China.	Fang Y	Frontiers in pediatrics	2021	PMID: 33763395
Putative second hit rare genetic variants in families with seemingly GBA-associated Parkinson's disease.	Aslam M	NPJ genomic medicine	2021	PMID: 33402667
Genetic characterization of the Albanian Gaucher disease patient population.	Cullufi P	JIMD reports	2020	PMID: 33473340
The GBA p.G85E mutation in Korean patients with non-neuronopathic Gaucher disease: founder and neuroprotective effects.	Kim YM	Orphanet journal of rare diseases	2020	PMID: 33176831
Genomic testing in 1019 individuals from 349 Pakistani families results in high diagnostic yield and clinical utility.	Cheema H	NPJ genomic medicine	2020	PMID: 33083013
Assessing Lysosomal Disorders in the NGS Era: Identification of Novel Rare Variants.	Encarnação M	International journal of molecular sciences	2020	PMID: 32883051
Association Between Glucocerebrosidase Mutations and Parkinson's Disease in Ireland.	Olszewska DA	Frontiers in neurology	2020	PMID: 32714263
A Large-Scale Full GBA1 Gene Screening in Parkinson's Disease in the Netherlands.	den Heijer JM	Movement disorders : official journal of the Movement Disorder Society	2020	PMID: 32618053
Newborn screening for Morquio disease and other lysosomal storage diseases: results from the 8-plex assay for 70,000 newborns.	Chien YH	Orphanet journal of rare diseases	2020	PMID: 32014045
High-frequency component in flash visual evoked potentials in type 3 Gaucher disease.	Oguri M	Brain & development	2020	PMID: 31561936
[Pathogenic gene variants and clinical phenotype features of 26 children with progressive myoclonic epilepsy].	Zhang J	Zhonghua er ke za zhi = Chinese journal of pediatrics	2019	PMID: 31216804
Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population.	Monies D	American journal of human genetics	2019	PMID: 31130284
GBA, Gaucher Disease, and Parkinson's Disease: From Genetic to Clinic to New Therapeutic Approaches.	Riboldi GM	Cells	2019	PMID: 31010158
POLG R964C and GBA L444P mutations in familial Parkinson's disease: Case report and literature review.	Hsieh PC	Brain and behavior	2019	PMID: 30941926
Generation of two iPSC lines derived from two unrelated patients with Gaucher disease.	Nagel M	Stem cell research	2019	PMID: 30606667
Clinical implementation of gene panel testing for lysosomal storage diseases.	Gheldof A	Molecular genetics & genomic medicine	2019	PMID: 30548430
Neuronopathic Gaucher disease presenting with microcytic hypochromic anemia.	Kim EA	International journal of hematology	2019	PMID: 30456712
Individualized screening for chaperone activity in Gaucher disease using multiple patient derived primary cell lines.	Ivanova MM	American journal of translational research	2018	PMID: 30662625
Biochemical and molecular characterization of adult patients with type I Gaucher disease and carrier frequency analysis of Leu444Pro - a common Gaucher disease mutation in India.	Sheth J	BMC medical genetics	2018	PMID: 30285649
Mutation analysis of Parkinson's disease genes in a Russian data set.	Emelyanov AK	Neurobiology of aging	2018	PMID: 30146349
Genotypes and phenotypes in 20 Chinese patients with type 2 Gaucher disease.	Kang L	Brain & development	2018	PMID: 29934114
A pilot screening of high-risk Gaucher disease children using dried blood spot methods in Shandong province of China.	Lei K	Orphanet journal of rare diseases	2018	PMID: 29625627
High-risk screening for Gaucher disease in patients with neurological symptoms.	Momosaki K	Journal of human genetics	2018	PMID: 29602947
Glucocerebrosidase gene variants are accumulated in idiopathic REM sleep behavior disorder.	Gámez-Valero A	Parkinsonism & related disorders	2018	PMID: 29487000
Improvement of life quality measured by Lansky Score after enzymatic replacement therapy in children with Gaucher disease type 1.	Cerón-Rodríguez M	Molecular genetics & genomic medicine	2018	PMID: 29471591
Clinical and molecular characteristics of patients with Gaucher disease in Southern China.	Feng Y	Blood cells, molecules & diseases	2018	PMID: 27865684
Genetic risk factors in Finnish patients with Parkinson's disease.	Ylönen S	Parkinsonism & related disorders	2017	PMID: 29029963
The L444P Gba1 mutation enhances alpha-synuclein induced loss of nigral dopaminergic neurons in mice.	Migdalska-Richards A	Brain : a journal of neurology	2017	PMID: 28969384
GBA mutations in Gaucher type I Venezuelan patients: ethnic origins and frequencies.	Gómez G	Journal of genetics	2017	PMID: 28947706
Lysosomal defects in ATP13A2 and GBA associated familial Parkinson's disease.	Sato S	Journal of neural transmission (Vienna, Austria : 1996)	2017	PMID: 28894968
GBA Analysis in Next-Generation Era: Pitfalls, Challenges, and Possible Solutions.	Zampieri S	The Journal of molecular diagnostics : JMD	2017	PMID: 28727984
Glucosylceramide and Glucosylsphingosine Quantitation by Liquid Chromatography-Tandem Mass Spectrometry to Enable In Vivo Preclinical Studies of Neuronopathic Gaucher Disease.	Hamler R	Analytical chemistry	2017	PMID: 28686011
Parkinson disease in Gaucher disease.	Rodriguez-Porcel F	Journal of clinical movement disorders	2017	PMID: 28546865
Specifically neuropathic Gaucher's mutations accelerate cognitive decline in Parkinson's.	Liu G	Annals of neurology	2016	PMID: 27717005
Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer.	Maxwell KN	American journal of human genetics	2016	PMID: 27153395
Long-term follow-up and sudden unexpected death in Gaucher disease type 3 in Egypt.	Abdelwahab M	Neurology. Genetics	2016	PMID: 27123474
Resequencing analysis of five Mendelian genes and the top genes from genome-wide association studies in Parkinson's Disease.	Benitez BA	Molecular neurodegeneration	2016	PMID: 27094865
Successful therapy for protein-losing enteropathy caused by chronic neuronopathic Gaucher disease.	Mhanni AA	Molecular genetics and metabolism reports	2015	PMID: 27014572
Gaucher disease types 1 and 3: Phenotypic characterization of large populations from the ICGG Gaucher Registry.	Grabowski GA	American journal of hematology	2015	PMID: 26096741
Clinical variability in neurohepatic syndrome due to combined mitochondrial DNA depletion and Gaucher disease.	Harvengt J	Molecular genetics and metabolism reports	2014	PMID: 27896091
Glucocerebrosidase gene mutations associated with Parkinson's disease: a meta-analysis in a Chinese population.	Chen J	PloS one	2014	PMID: 25535748
Disease variants in genomes of 44 centenarians.	Freudenberg-Hua Y	Molecular genetics & genomic medicine	2014	PMID: 25333069
Glucocerebrosidase mutations in primary parkinsonism.	Asselta R	Parkinsonism & related disorders	2014	PMID: 25249066
Novel mutations in the glucocerebrosidase gene of Indian patients with Gaucher disease.	Ankleshwaria C	Journal of human genetics	2014	PMID: 24522292
Recurrent pulmonary aspergillosis and mycobacterial infection in an unsplenectomized patient with type 1 Gaucher disease.	Machaczka M	Upsala journal of medical sciences	2014	PMID: 24195576
Clinicogenetic study of GBA mutations in patients with familial Parkinson's disease.	Li Y	Neurobiology of aging	2014	PMID: 24126159
Clinical profiles of Parkinson's disease associated with common leucine-rich repeat kinase 2 and glucocerebrosidase genetic variants in Chinese individuals.	Wang C	Neurobiology of aging	2014	PMID: 24095219
Functional analysis of 11 novel GBA alleles.	Malini E	European journal of human genetics : EJHG	2014	PMID: 24022302
Unfolded protein response in Gaucher disease: from human to Drosophila.	Maor G	Orphanet journal of rare diseases	2013	PMID: 24020503
A common and two novel GBA mutations in Thai patients with Gaucher disease.	Tammachote R	Journal of human genetics	2013	PMID: 23719189
Mutations in GBA and risk of Parkinson's disease: a meta-analysis based on 25 case-control studies.	Mao X	Neurological research	2013	PMID: 23676350
Corneal manifestations and in vivo confocal microscopy of Gaucher disease.	Geens S	Cornea	2013	PMID: 23635853
A multicenter study of glucocerebrosidase mutations in dementia with Lewy bodies.	Nalls MA	JAMA neurology	2013	PMID: 23588557
The L444P GBA mutation is associated with early-onset Parkinson's disease in Mexican Mestizos.	González-Del Rincón Mde L	Clinical genetics	2013	PMID: 23448517
Novel mutations in the glucocerebrosidase gene of brazilian patients with Gaucher disease.	Siebert M	JIMD reports	2013	PMID: 23430543
Histone deacetylase inhibitors increase glucocerebrosidase activity in Gaucher disease by modulation of molecular chaperones.	Yang C	Proceedings of the National Academy of Sciences of the United States of America	2013	PMID: 23277556
An empirical estimate of carrier frequencies for 400+ causal Mendelian variants: results from an ethnically diverse clinical sample of 23,453 individuals.	Lazarin GA	Genetics in medicine : official journal of the American College of Medical Genetics	2013	PMID: 22975760
A germline or de novo mutation in two families with Gaucher disease: implications for recessive disorders.	Saranjam H	European journal of human genetics : EJHG	2013	PMID: 22713811
Association of Common Variants in the Glucocerebrosidase Gene with High Susceptibility to Parkinson's Disease among Chinese.	Zhang X	The Chinese journal of physiology	2012	PMID: 23286447
Glucocerebrosidase L444P mutation confers genetic risk for Parkinson's disease in central China.	Wang Y	Behavioral and brain functions : BBF	2012	PMID: 23227814
Gaucher disease paradigm: from ERAD to comorbidity.	Bendikov-Bar I	Human mutation	2012	PMID: 22623374
Progressive mesenteric lymphadenopathy with protein-losing enteropathy; a devastating complication in Gaucher disease.	Lee BH	Molecular genetics and metabolism	2012	PMID: 22227073
Gaucher disease: a pyrosequencing frequency analysis of the N370S and L444P mutations in the Spanish population.	García-Rodríguez B	Clinical genetics	2012	PMID: 22220748
Glucocerebrosidase N370S and L444P mutations as risk factors for Parkinson's disease in Brazilian patients.	Guimarães Bde C	Parkinsonism & related disorders	2012	PMID: 22192918
Histone deacetylase inhibitors prevent the degradation and restore the activity of glucocerebrosidase in Gaucher disease.	Lu J	Proceedings of the National Academy of Sciences of the United States of America	2011	PMID: 22160715
Inhibition of endoplasmic reticulum-associated degradation rescues native folding in loss of function protein misfolding diseases.	Wang F	The Journal of biological chemistry	2011	PMID: 22006919
Glucocerebrosidase mutations in a French-Canadian Parkinson's disease cohort.	Noreau A	The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques	2011	PMID: 21856586
β-Glucocerebrosidase gene mutations in two cohorts of Greek patients with sporadic Parkinson's disease.	Moraitou M	Molecular genetics and metabolism	2011	PMID: 21745757
Aggregation of α-synuclein in brain samples from subjects with glucocerebrosidase mutations.	Choi JH	Molecular genetics and metabolism	2011	PMID: 21742527
Gaucher disease glucocerebrosidase and α-synuclein form a bidirectional pathogenic loop in synucleinopathies.	Mazzulli JR	Cell	2011	PMID: 21700325
Lacidipine remodels protein folding and Ca 2+ homeostasis in Gaucher's disease fibroblasts: a mechanism to rescue mutant glucocerebrosidase.	Wang F	Chemistry & biology	2011	PMID: 21700212
Acid β-glucosidase mutants linked to Gaucher disease, Parkinson disease, and Lewy body dementia alter α-synuclein processing.	Cullen V	Annals of neurology	2011	PMID: 21472771
Carrier testing for severe childhood recessive diseases by next-generation sequencing.	Bell CJ	Science translational medicine	2011	PMID: 21228398
Characterization of the ERAD process of the L444P mutant glucocerebrosidase variant.	Bendikov-Bar I	Blood cells, molecules & diseases	2011	PMID: 21106416
Mutational analysis of GIGYF2, ATP13A2 and GBA genes in Brazilian patients with early-onset Parkinson's disease.	Dos Santos AV	Neuroscience letters	2010	PMID: 20816920
Association between GBA L444P mutation and sporadic Parkinson's disease from Mainland China.	Mao XY	Neuroscience letters	2010	PMID: 20004703
Glucocerebrosidase mutations in clinical and pathologically proven Parkinson's disease.	Neumann J	Brain : a journal of neurology	2009	PMID: 19286695
Mutations in GBA are associated with familial Parkinson disease susceptibility and age at onset.	Nichols WC	Neurology	2009	PMID: 18987351
The need for appropriate genotyping strategies for glucocerebrosidase mutations in cohorts with Parkinson disease.	Gutti U	Archives of neurology	2008	PMID: 18541817
Uniparental disomy of chromosome 1 causing concurrent Charcot-Marie-Tooth and Gaucher disease Type 3.	Benko WS	Neurology	2008	PMID: 18347322
Gaucher disease: mutation and polymorphism spectrum in the glucocerebrosidase gene (GBA).	Hruska KS	Human mutation	2008	PMID: 18338393
Glucocerebrosidase gene mutations: a risk factor for Lewy body disorders.	Mata IF	Archives of neurology	2008	PMID: 18332251
LIMP-2 is a receptor for lysosomal mannose-6-phosphate-independent targeting of beta-glucocerebrosidase.	Reczek D	Cell	2007	PMID: 18022370
Mutations in the glucocerebrosidase gene are associated with early-onset Parkinson disease.	Clark LN	Neurology	2007	PMID: 17875915
Glucocerebrosidase mutations and risk of Parkinson disease in Chinese patients.	Tan EK	Archives of neurology	2007	PMID: 17620502
Mutation analysis and genotype/phenotype relationships of Gaucher disease patients in Spain.	Alfonso P	Journal of human genetics	2007	PMID: 17427031
Acute neuronopathic Gaucher disease complicated by fatal gastrointestinal bleeding.	Hoffmann B	Neuropediatrics	2006	PMID: 16967369
Analyses of variant acid beta-glucosidases: effects of Gaucher disease mutations.	Liou B	The Journal of biological chemistry	2006	PMID: 16293621
Identification and functional characterization of five novel mutant alleles in 58 Italian patients with Gaucher disease type 1.	Miocić S	Human mutation	2005	PMID: 15605411
Functional analysis of 13 GBA mutant alleles identified in Gaucher disease patients: Pathogenic changes and "modifier" polymorphisms.	Montfort M	Human mutation	2004	PMID: 15146461
Expression and functional characterization of mutated glucocerebrosidase alleles causing Gaucher disease in Spanish patients.	Alfonso P	Blood cells, molecules & diseases	2004	PMID: 14757438
Type II Gaucher disease: compound heterozygote with RecNciI and L444P mutations.	Lee YS	Journal of tropical pediatrics	2001	PMID: 11336129
Analysis and classification of 304 mutant alleles in patients with type 1 and type 3 Gaucher disease.	Koprivica V	American journal of human genetics	2000	PMID: 10796875
Myoclonus from selective dentate nucleus degeneration in type 3 Gaucher disease.	Verghese J	Archives of neurology	2000	PMID: 10714667
Glucocerebrosidase gene mutations in patients with type 2 Gaucher disease.	Stone DL	Human mutation	2000	PMID: 10649495
Glucocerebrosidase genotype of Gaucher patients in The Netherlands: limitations in prognostic value.	Boot RG	Human mutation	1997	PMID: 9375849
The clinical, molecular, and pathological characterisation of a family with two cases of lethal perinatal type 2 Gaucher disease.	Sidransky E	Journal of medical genetics	1996	PMID: 8929950
Analysis of human acid beta-glucosidase by site-directed mutagenesis and heterologous expression.	Grace ME	The Journal of biological chemistry	1994	PMID: 8294487
RecTL: a complex allele of the glucocerebrosidase gene associated with a mild clinical course of Gaucher disease.	Zimran A	American journal of medical genetics	1994	PMID: 8160756
New Gaucher disease mutations in exon 10: a novel L444R mutation produces a new NciI site the same as L444P.	Uchiyama A	Human molecular genetics	1994	PMID: 7981693
Heterogeneity of mutations in the acid beta-glucosidase gene of Gaucher disease patients.	Latham TE	DNA and cell biology	1991	PMID: 1899336
Gaucher disease type III (Norrbottnian type) is caused by a single mutation in exon 10 of the glucocerebrosidase gene.	Dahl N	American journal of human genetics	1990	PMID: 2378352
Complex alleles of the acid beta-glucosidase gene in Gaucher disease.	Latham T	American journal of human genetics	1990	PMID: 2349952
Genotype assignment in Gaucher disease by selective amplification of the active glucocerebrosidase gene.	Firon N	American journal of human genetics	1990	PMID: 2309702
Sequence of two alleles responsible for Gaucher disease.	Hong CM	DNA and cell biology	1990	PMID: 1972019
Prediction of severity of Gaucher's disease by identification of mutations at DNA level.	Zimran A	Lancet (London, England)	1989	PMID: 2569551
Characterization of mutations in Gaucher patients by cDNA cloning.	Wigderson M	American journal of human genetics	1989	PMID: 2464926
Genetic heterogeneity in type 1 Gaucher disease: multiple genotypes in Ashkenazic and non-Ashkenazic individuals.	Tsuji S	Proceedings of the National Academy of Sciences of the United States of America	1988	PMID: 3353383
A mutation in the human glucocerebrosidase gene in neuronopathic Gaucher's disease.	Tsuji S	The New England journal of medicine	1987	PMID: 2880291
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GBA	-	-	-	-
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/b929ba0d-8dd5-49ad-82bc-61c570246b2f	-	-	-	-
-	-	-	-	DOI: 10.1056/NEJM198703053161002
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Text-mined citations for rs421016 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000157.4(GBA1):c.1448T>C (p.Leu483Pro)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs421016 ...