VCV000177834.16 - ClinVar

NM_000169.3(GLA):c.1117G>A (p.Gly373Ser)

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.

(6)

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_000169.3(GLA):c.1117G>A (p.Gly373Ser)

Variation ID: 177834 Accession: VCV000177834.16

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq22.1 X: 101397982 (GRCh38) [ NCBI UCSC ] X: 100652970 (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	May 29, 2016	Feb 4, 2024	Aug 5, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_000169.3:c.1117G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000160.1:p.Gly373Ser	missense
NM_001199973.2:c.300+2525C>T		intron variant
NM_001199974.2:c.177+6160C>T		intron variant
NM_001406747.1:c.1240G>A	NP_001393676.1:p.Gly414Ser	missense
NR_164783.1:n.1196G>A		non-coding transcript variant
NR_176252.1:n.1047G>A		non-coding transcript variant
NR_176253.1:n.1254G>A		non-coding transcript variant
NC_000023.11:g.101397982C>T
NC_000023.10:g.100652970C>T
NG_007119.1:g.14982G>A
LRG_672:g.14982G>A
LRG_672t1:c.1117G>A	LRG_672p1:p.Gly373Ser
	P06280:p.Gly373Ser

... more HGVS ... less HGVS

Protein change

G373S, G414S

Other names

Canonical SPDI

NC_000023.11:101397981:C:T

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

ClinGen: CA021403 UniProtKB: P06280#VAR_012437 dbSNP: rs727504348 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.
GLA		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	7	1257
RPL36A-HNRNPH2	-	-	-	GRCh38 GRCh37	-	1295

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.
Fabry disease	Pathogenic/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Aug 5, 2022	RCV000154469.9
not provided	Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Aug 17, 2020	RCV000727357.9
Fabry disease Hypertrophic cardiomyopathy	Likely pathogenic (1)	no assertion criteria provided	Feb 11, 2013	RCV000844704.5

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 (Jun 18, 2018)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000707842.2 First in ClinVar: May 29, 2016 Last updated: Dec 15, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GLA Number of individuals with the variant: 4 Sex: mixed
Likely pathogenic (Aug 17, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002018434.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Fabry disease Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001141976.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020
Likely pathogenic (Jul 15, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Fabry disease Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002054372.1 First in ClinVar: Jan 12, 2022 Last updated: Jan 12, 2022
Pathogenic (Aug 05, 2022)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Fabry disease Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000917447.2 First in ClinVar: Jun 02, 2019 Last updated: Sep 17, 2022	Publications: PubMed (9) PubMed: 17555407‚ 24386359‚ 25382311‚ 25611685‚ 27532257‚ 7575533‚ 28649509‚ 30988410‚ 34401344 Comment: Variant summary: GLA c.1117G>A (p.Gly373Ser) results in a non-conservative amino acid change located in the Alpha galactosidase A, C-terminal beta-sandwich domain (IPR035373) of the encoded … (more) Variant summary: GLA c.1117G>A (p.Gly373Ser) results in a non-conservative amino acid change located in the Alpha galactosidase A, C-terminal beta-sandwich domain (IPR035373) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183441 control chromosomes (gnomAD). c.1117G>A has been reported in the literature in multiple individuals affected with classic- or later onset Fabry Disease (e.g. Okumiya_1995, Thurberg_2017, Coutinho_2017, Kobayashi_2019, Bichet_2021) and also with hypertrophic cardiomyopathy (Alfares_2015, Walsh_2017). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated severely decreased enzyme activity (Okumiya_1995, Ishii_2007, Bichet_2021). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=1) / likely pathogenic (n=3). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Likely pathogenic (Feb 11, 2013)	no assertion criteria provided Method: clinical testing	Hypertrophic cardiomyopathy Fabry disease (X-linked inheritance) Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000204138.3 First in ClinVar: Jan 31, 2015 Last updated: May 29, 2016	Publications: PubMed (3) PubMed: 7575533‚ 17555407‚ 11914245 Comment: proposed classification - variant undergoing re-assessment, contact laboratory Number of individuals with the variant: 1

Comment:

Variant summary: GLA c.1117G>A (p.Gly373Ser) results in a non-conservative amino acid change located in the Alpha galactosidase A, C-terminal beta-sandwich domain (IPR035373) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183441 control chromosomes (gnomAD). c.1117G>A has been reported in the literature in multiple individuals affected with classic- or later onset Fabry Disease (e.g. Okumiya_1995, Thurberg_2017, Coutinho_2017, Kobayashi_2019, Bichet_2021) and also with hypertrophic cardiomyopathy (Alfares_2015, Walsh_2017). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated severely decreased enzyme activity (Okumiya_1995, Ishii_2007, Bichet_2021). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=1) / likely pathogenic (n=3). Based on the evidence outlined above, the variant was 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
Long-term follow-up of renal function in patients treated with migalastat for Fabry disease.	Bichet DG	Molecular genetics and metabolism reports	2021	PMID: 34401344
Mutation spectrum of α-Galactosidase gene in Japanese patients with Fabry disease.	Kobayashi M	Journal of human genetics	2019	PMID: 30988410
Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples.	Walsh R	Genetics in medicine : official journal of the American College of Medical Genetics	2017	PMID: 27532257
Fabry disease: Four case reports of meningioma and a review of the literature on other malignancies.	Thurberg BL	Molecular genetics and metabolism reports	2016	PMID: 28649509
Results of clinical genetic testing of 2,912 probands with hypertrophic cardiomyopathy: expanded panels offer limited additional sensitivity.	Alfares AA	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25611685
Molecular damage in Fabry disease: characterization and prediction of alpha-galactosidase A pathological mutations.	Riera C	Proteins	2015	PMID: 25382311
Comparative study of structural changes caused by different substitutions at the same residue on α-galactosidase A.	Saito S	PloS one	2013	PMID: 24386359
Mutant alpha-galactosidase A enzymes identified in Fabry disease patients with residual enzyme activity: biochemical characterization and restoration of normal intracellular processing by 1-deoxygalactonojirimycin.	Ishii S	The Biochemical journal	2007	PMID: 17555407
Prevalence of Anderson-Fabry disease in male patients with late onset hypertrophic cardiomyopathy.	Sachdev B	Circulation	2002	PMID: 11914245
Galactose stabilizes various missense mutants of alpha-galactosidase in Fabry disease.	Okumiya T	Biochemical and biophysical research communications	1995	PMID: 7575533
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GLA	-	-	-	-
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Text-mined citations for rs727504348 ...

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 Sep 17, 2024

ClinVar Genomic variation as it relates to human health

NM_000169.3(GLA):c.1117G>A (p.Gly373Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs727504348 ...