VCV000088770.19 - ClinVar

NM_000235.4(LIPA):c.260G>T (p.Gly87Val)

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.

(11)

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/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000235.4(LIPA):c.260G>T (p.Gly87Val)

Variation ID: 88770 Accession: VCV000088770.19

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 10q23.31 10: 89228368 (GRCh38) [ NCBI UCSC ] 10: 90988125 (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	Sep 16, 2016	Jun 17, 2024	Mar 17, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000235.4:c.260G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000226.2:p.Gly87Val	missense
NM_001127605.3:c.260G>T	NP_001121077.1:p.Gly87Val	missense
NM_001288979.2:c.-89G>T		5 prime UTR
NC_000010.11:g.89228368C>A
NC_000010.10:g.90988125C>A
NG_008194.1:g.28536G>T

... more HGVS ... less HGVS

Protein change

G87V

Other names

Canonical SPDI

NC_000010.11:89228367:C:A

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.

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

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

Links

ClinGen: CA347038 Genetic Testing Registry (GTR): GTR000327733 dbSNP: rs587778878 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.
LIPA		-	-	GRCh38 GRCh37	654	686

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.
Lysosomal acid lipase deficiency	Pathogenic/Likely pathogenic (6)	criteria provided, multiple submitters, no conflicts	May 8, 2023	RCV000191997.21
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	May 18, 2022	RCV001269917.11
Wolman disease	Pathogenic (1)	criteria provided, single submitter	Jan 13, 2024	RCV001376576.13
Cholesteryl ester storage disease	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Mar 17, 2024	RCV003987346.4

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.
Likely pathogenic (Jan 19, 2018)	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) Method: clinical testing	Cholesteryl ester storage disease Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000797291.1 First in ClinVar: Mar 16, 2017 Last updated: Mar 16, 2017	Publications: PubMed (4) PubMed: 23583223‚ 8894696‚ 11441129‚ 9684740
Pathogenic (May 19, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics and Genomics, Karolinska University Hospital Accession: SCV001450275.1 First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020	Number of individuals with the variant: 5
Pathogenic (May 18, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002756618.1 First in ClinVar: Dec 03, 2022 Last updated: Dec 03, 2022	Comment: Published functional studies demonstrate a damaging effect due to significantly reduced enzyme activity compared to wildtype (Pagani et al., 1998; Zschenker et al., 2001; Vinje … (more) Published functional studies demonstrate a damaging effect due to significantly reduced enzyme activity compared to wildtype (Pagani et al., 1998; Zschenker et al., 2001; Vinje et al., 2018; Vinje et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26225414, 23424026, 11441129, 28374935, 31589614, 8894696, 31131398, 22138108, 30684275, 9684740, 33857477, 29196158, 21291321) (less)
Pathogenic (Feb 01, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Cholesteryl ester storage disease Affected status: no Allele origin: germline	Laboratory of Medical Genetics, National & Kapodistrian University of Athens Accession: SCV005051851.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024
Pathogenic (Dec 30, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cholesteryl ester storage disease Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002810889.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (May 08, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Cholesteryl ester storage disease Affected status: yes Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV003924300.1 First in ClinVar: May 20, 2023 Last updated: May 20, 2023
Pathogenic (Jan 13, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Wolman disease Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000831923.6 First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024	Publications: PubMed (7) PubMed: 28492532‚ 2129132‚ 8894696‚ 11441129‚ 23424026‚ 28374935‚ 9684740 Comment: This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 87 of the LIPA protein (p.Gly87Val). … (more) This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 87 of the LIPA protein (p.Gly87Val). This variant is present in population databases (rs587778878, gnomAD 0.003%). This missense change has been observed in individuals with cholesteryl ester storage disease (CESD) or Wolman disease (PMID: 2129132, 8894696, 11441129, 23424026, 28374935). ClinVar contains an entry for this variant (Variation ID: 88770). 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) performed at Invitae indicates that this missense variant is expected to disrupt LIPA protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects LIPA function (PMID: 9684740, 11441129). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Mar 17, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Cholesteryl ester storage disease Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004804781.2 First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024
Pathogenic (-)	no assertion criteria provided Method: clinical testing	Wolman disease Affected status: unknown Allele origin: germline	FirmaLab, FirmaLab Accession: SCV000106039.1 First in ClinVar: Mar 16, 2017 Last updated: Mar 16, 2017
Pathogenic (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Lysosomal acid lipase deficiency Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001453550.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
not provided (-)	no classification provided Method: literature only	Lysosomal acid lipase deficiency Affected status: yes Allele origin: germline	GeneReviews Accession: SCV000246263.3 First in ClinVar: Oct 05, 2015 Last updated: Oct 01, 2022	Publications: PubMed (2) PubMed: 21291321‚ 8894696 BookShelf: NBK305870 BookShelf: NBK305870
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Comment:

Published functional studies demonstrate a damaging effect due to significantly reduced enzyme activity compared to wildtype (Pagani et al., 1998; Zschenker et al., 2001; Vinje et al., 2018; Vinje et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26225414, 23424026, 11441129, 28374935, 31589614, 8894696, 31131398, 22138108, 30684275, 9684740, 33857477, 29196158, 21291321)

Comment:

This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 87 of the LIPA protein (p.Gly87Val). This variant is present in population databases (rs587778878, gnomAD 0.003%). This missense change has been observed in individuals with cholesteryl ester storage disease (CESD) or Wolman disease (PMID: 2129132, 8894696, 11441129, 23424026, 28374935). ClinVar contains an entry for this variant (Variation ID: 88770). 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) performed at Invitae indicates that this missense variant is expected to disrupt LIPA protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects LIPA function (PMID: 9684740, 11441129). For these reasons, this variant has been classified as Pathogenic.

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
Prenatal sonographic findings in a case of Wolman's disease.	Blitz MJ	Journal of clinical ultrasound : JCU	2018	PMID: 28374935
Lysosomal Acid Lipase Deficiency.	Adam MP	-	2016	PMID: 26225414
Unfavorable outcome of hematopoietic stem cell transplantation in two siblings with Wolman disease due to graft failure and hepatic complications.	Yanir A	Molecular genetics and metabolism	2013	PMID: 23583223
Frequency of the cholesteryl ester storage disease common LIPA E8SJM mutation (c.894G>A) in various racial and ethnic groups.	Scott SA	Hepatology (Baltimore, Md.)	2013	PMID: 23424026
Wolman disease (LIPA p.G87V) genotype frequency in people of Iranian-Jewish ancestry.	Valles-Ayoub Y	Genetic testing and molecular biomarkers	2011	PMID: 21291321
Characterization of lysosomal acid lipase mutations in the signal peptide and mature polypeptide region causing Wolman disease.	Zschenker O	Journal of lipid research	2001	PMID: 11441129
New lysosomal acid lipase gene mutants explain the phenotype of Wolman disease and cholesteryl ester storage disease.	Pagani F	Journal of lipid research	1998	PMID: 9684740
Expression of lysosomal acid lipase mutants detected in three patients with cholesteryl ester storage disease.	Pagani F	Human molecular genetics	1996	PMID: 8894696
Permeability of gentamicin and polymyxin B into the inside of Bacillus subtilis spores.	Fujita Y	Microbiology and immunology	1990	PMID: 2129132

Text-mined citations for rs587778878 ...

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_000235.4(LIPA):c.260G>T (p.Gly87Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs587778878 ...