VCV000202191.39 - ClinVar

NM_000404.4(GLB1):c.1577dup (p.Trp527fs)

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.

(8)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000404.4(GLB1):c.1577dup (p.Trp527fs)

Variation ID: 202191 Accession: VCV000202191.39

Type and length

Duplication, 1 bp

Location

Cytogenetic: 3p22.3 3: 33014212-33014213 (GRCh38) [ NCBI UCSC ] 3: 33055704-33055705 (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	Jul 3, 2015	Oct 20, 2024	Dec 30, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000404.4:c.1577dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000395.3:p.Trp527fs	frameshift
NM_000404.4:c.1577dupG MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000404.2:c.1577dupG
NM_001079811.3:c.1487dup	NP_001073279.2:p.Trp497fs	frameshift
NM_001135602.3:c.1184dup	NP_001129074.2:p.Trp396fs	frameshift
NM_001317040.2:c.1721dup	NP_001303969.2:p.Trp575fs	frameshift
NM_001393580.1:c.1577dup	NP_001380509.1:p.Trp527fs	frameshift
NC_000003.12:g.33014218dup
NC_000003.11:g.33055710dup
NG_009005.1:g.87990dup

... more HGVS ... less HGVS

Protein change

W527fs, W575fs, W497fs, W396fs

Other names

1622_1627insG

Canonical SPDI

NC_000003.12:33014212:CCCCCC:CCCCCCC

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.

Links

dbSNP: rs794729217 ClinGen: CA203855 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.
GLB1		-	-	GRCh38 GRCh37	1058	1171

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.
Infantile GM1 gangliosidosis	not provided (1)	no classification provided	-	RCV000184037.5
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jun 1, 2018	RCV000627406.23
GM1 gangliosidosis Mucopolysaccharidosis, MPS-IV-B	Pathogenic (1)	criteria provided, single submitter	Dec 30, 2023	RCV000798976.5
GM1 gangliosidosis type 2	Pathogenic (1)	criteria provided, single submitter	May 28, 2019	RCV000987139.2
GM1 gangliosidosis	Pathogenic (1)	criteria provided, single submitter	Sep 17, 2020	RCV001260322.2
GM1 gangliosidosis type 3	Pathogenic (1)	criteria provided, single submitter	Oct 17, 2022	RCV003137707.2
GLB1-related disorder	Pathogenic (1)	criteria provided, single submitter	Jan 1, 2019	RCV004528961.1

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.
Pathogenic (Apr 03, 2018)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000748400.3 First in ClinVar: May 21, 2018 Last updated: May 21, 2018	Comment: The c.1577dupG variant in the GLB1 gene has been reported previously using alternate nomenclature (1622-1627insG) in association with autosomal recessive GM1-gangliosidosis type I (Silva et … (more) The c.1577dupG variant in the GLB1 gene has been reported previously using alternate nomenclature (1622-1627insG) in association with autosomal recessive GM1-gangliosidosis type I (Silva et al., 1999). This variant is common in individuals from Brazil, having been identified in 42.5% of alleles from affected individuals in one study (Silva et al., 1999). The c.1577dupG variant causes a frameshift starting with codon Tryptophan 527, changes this amino acid to a Leucine residue, and creates a premature Stop codon at position 5 of the new reading frame, denoted p.Trp527LeufsX5. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.1577dupG variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret c.1577dupG as a pathogenic variant. (less)
Pathogenic (Sep 17, 2020)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	GM1 gangliosidosis Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV001437247.1 First in ClinVar: Oct 08, 2020 Last updated: Oct 08, 2020	Publications: PubMed (2) PubMed: 10338095‚ 31761138 Comment: Variant summary: GLB1 c.1577dupG (p.Trp527LeufsX5) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more) Variant summary: GLB1 c.1577dupG (p.Trp527LeufsX5) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 8.1e-06 in 247798 control chromosomes (gnomAD). c.1577dupG has been reported in the literature, in the compound heterozygous and homozygous state, in multiple individuals affected with GM1 Gangliosidosis (e.g. Silva_1999, Arash-Kaps_2019). These data indicate that the variant is very likely to be associated with disease. Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Jan 01, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	GLB1-Related Disorders Affected status: yes Allele origin: inherited	Genomic Research Center, Shahid Beheshti University of Medical Sciences Accession: SCV000923441.1 First in ClinVar: Jun 17, 2019 Last updated: Jun 17, 2019	Number of individuals with the variant: 1 Geographic origin: Iran
Pathogenic (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	GM1 gangliosidosis type 2 Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001136360.1 First in ClinVar: Jan 11, 2020 Last updated: Jan 11, 2020
Pathogenic (Oct 17, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	GM1 gangliosidosis type 3 Affected status: yes Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV003807647.1 First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023	Comment: ACMG classification criteria: PVS1 very strong, PM2 moderated, PM3 very strong Number of individuals with the variant: 1 Clinical Features: Scoliosis (present) , Hypertonia (present) , Generalized dystonia (present) , Flexion contracture (present) Geographic origin: Brazil Method: Paired-end whole-genome sequencing
Pathogenic (Dec 30, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Mucopolysaccharidosis, MPS-IV-B GM1 gangliosidosis 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: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000938621.3 First in ClinVar: Aug 14, 2019 Last updated: Feb 28, 2024	Publications: PubMed (6) PubMed: 18524657‚ 10338095‚ 15986423‚ 16941474‚ 17309651‚ 25936995 Comment: This sequence change creates a premature translational stop signal (p.Trp527Leufs5) in the GLB1 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Trp527Leufs5) in the GLB1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GLB1 are known to be pathogenic (PMID: 18524657). This variant is present in population databases (rs794729217, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with GM1 gangliosidosis (PMID: 10338095, 15986423, 16941474, 17309651, 25936995). This variant is also known as c.1622_1627insG,1606_1611insG, c.1577 1578insG, or c.1572_1577insG. ClinVar contains an entry for this variant (Variation ID: 202191). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Jun 01, 2018)	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: SCV001248011.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 3
not provided (-)	no classification provided Method: literature only	Infantile GM1 gangliosidosis Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV001821205.2 First in ClinVar: Sep 08, 2021 Last updated: Oct 01, 2022	Publications: PubMed (1) PubMed: 21637542 Comment: High prevalence in Brazilian population; associated with GM1 infantile form

Comment:

The c.1577dupG variant in the GLB1 gene has been reported previously using alternate nomenclature (1622-1627insG) in association with autosomal recessive GM1-gangliosidosis type I (Silva et al., 1999). This variant is common in individuals from Brazil, having been identified in 42.5% of alleles from affected individuals in one study (Silva et al., 1999). The c.1577dupG variant causes a frameshift starting with codon Tryptophan 527, changes this amino acid to a Leucine residue, and creates a premature Stop codon at position 5 of the new reading frame, denoted p.Trp527LeufsX5. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.1577dupG variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret c.1577dupG as a pathogenic variant.

Comment:

Variant summary: GLB1 c.1577dupG (p.Trp527LeufsX5) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 8.1e-06 in 247798 control chromosomes (gnomAD). c.1577dupG has been reported in the literature, in the compound heterozygous and homozygous state, in multiple individuals affected with GM1 Gangliosidosis (e.g. Silva_1999, Arash-Kaps_2019). These data indicate that the variant is very likely to be associated with disease. Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

This sequence change creates a premature translational stop signal (p.Trp527Leufs*5) in the GLB1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GLB1 are known to be pathogenic (PMID: 18524657). This variant is present in population databases (rs794729217, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with GM1 gangliosidosis (PMID: 10338095, 15986423, 16941474, 17309651, 25936995). This variant is also known as c.1622_1627insG,1606_1611insG, c.1577 1578insG, or c.1572_1577insG. ClinVar contains an entry for this variant (Variation ID: 202191). 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
The Clinical and Molecular Spectrum of GM1 Gangliosidosis.	Arash-Kaps L	The Journal of pediatrics	2019	PMID: 31761138
Recurrent and novel GLB1 mutations in India.	Bidchol AM	Gene	2015	PMID: 25936995
Population analysis of the GLB1 gene in South Brazil.	Baiotto C	Genetics and molecular biology	2011	PMID: 21637542
GM1 gangliosidosis: review of clinical, molecular, and therapeutic aspects.	Brunetti-Pierri N	Molecular genetics and metabolism	2008	PMID: 18524657
Identification of 14 novel GLB1 mutations, including five deletions, in 19 patients with GM1 gangliosidosis from South America.	Santamaria R	Clinical genetics	2007	PMID: 17309651
Twenty-one novel mutations in the GLB1 gene identified in a large group of GM1-gangliosidosis and Morquio B patients: possible common origin for the prevalent p.R59H mutation among gypsies.	Santamaria R	Human mutation	2006	PMID: 16941474
Dystonia and parkinsonism in GM1 type 3 gangliosidosis.	Roze E	Movement disorders : official journal of the Movement Disorder Society	2005	PMID: 15986423
Six novel beta-galactosidase gene mutations in Brazilian patients with GM1-gangliosidosis.	Silva CM	Human mutation	1999	PMID: 10338095

Text-mined citations for rs794729217 ...

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_000404.4(GLB1):c.1577dup (p.Trp527fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs794729217 ...