VCV000042452.25 - ClinVar

NM_000169.3(GLA):c.1153A>G (p.Thr385Ala)

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.

(12)

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.

Benign/Likely benign

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.1153A>G (p.Thr385Ala)

Variation ID: 42452 Accession: VCV000042452.25

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq22.1 X: 101397946 (GRCh38) [ NCBI UCSC ] X: 100652934 (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	Mar 8, 2017	May 1, 2024	Jan 24, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000169.3:c.1153A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000160.1:p.Thr385Ala	missense
NM_001199973.2:c.300+2489T>C		intron variant
NM_001199974.2:c.177+6124T>C		intron variant
NM_001406747.1:c.1276A>G	NP_001393676.1:p.Thr426Ala	missense
NR_164783.1:n.1232A>G		non-coding transcript variant
NR_176252.1:n.1083A>G		non-coding transcript variant
NR_176253.1:n.1290A>G		non-coding transcript variant
NC_000023.11:g.101397946T>C
NC_000023.10:g.100652934T>C
NG_007119.1:g.15018A>G
LRG_672:g.15018A>G
LRG_672t1:c.1153A>G	LRG_672p1:p.Thr385Ala

... more HGVS ... less HGVS

Protein change

T385A, T426A

Other names

Canonical SPDI

NC_000023.11:101397945:T:C

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

effect on protein activity; Variation Ontology [ VariO:0053]

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.

0.00053 (C)

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

The Genome Aggregation Database (gnomAD) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00003

1000 Genomes Project 0.00053

The Genome Aggregation Database (gnomAD), exomes 0.00056

Exome Aggregation Consortium (ExAC) 0.00060

1000 Genomes Project 30x 0.00062

Links

ClinGen: CA021417 dbSNP: rs397515869 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	Benign/Likely benign (6)	criteria provided, multiple submitters, no conflicts	Jan 24, 2024	RCV000613255.17
not provided	Likely benign (3)	no assertion criteria provided	-	RCV001573054.5
Cardiovascular phenotype	Benign (1)	criteria provided, single submitter	Jan 7, 2020	RCV002345271.3
not specified	Likely benign (2)	criteria provided, multiple submitters, no conflicts	Nov 30, 2016	RCV000035301.8

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 benign (Nov 30, 2016)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000207836.8 First in ClinVar: Feb 24, 2015 Last updated: Mar 08, 2017	Comment: This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more) This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
Likely benign (Mar 18, 2015)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000058949.5 First in ClinVar: May 03, 2013 Last updated: Mar 08, 2017	Publications: PubMed (2) PubMed: 12175777‚ 23935525 Comment: p.Thr385Ala in exon 7 of GLA: This variant is not expected to be disease causing on its own because it has been identified in 0.5% … (more) p.Thr385Ala in exon 7 of GLA: This variant is not expected to be disease causing on its own because it has been identified in 0.5% (53/10122; including 36 males ) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://e xac.broadinstitute.org; dbSNP rs397515869). Furthermore, it has been identified by our laboratory in 2 adults (1 male, 1 female) with DCM and did not segregate with disease in either family. (less) Number of individuals with the variant: 4
Likely benign (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Fabry disease Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001141975.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020
Benign (Oct 26, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Fabry disease Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000914047.1 First in ClinVar: May 20, 2019 Last updated: May 20, 2019
Benign (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: SCV002054326.1 First in ClinVar: Jan 12, 2022 Last updated: Jan 12, 2022
Likely benign (Jan 24, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Fabry disease Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000748702.7 First in ClinVar: Apr 09, 2018 Last updated: Feb 28, 2024
Benign (Jan 07, 2020)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002622189.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (2) PubMed: 12175777‚ 23935525 Comment: This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more) This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Likely benign (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Fabry disease Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001457721.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	Fabry disease Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV000734722.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Study: VKGL Data-share Consensus Accession: SCV001798360.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001967678.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001979050.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021
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Comment:

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Comment:

p.Thr385Ala in exon 7 of GLA: This variant is not expected to be disease causing on its own because it has been identified in 0.5% (53/10122; including 36 males ) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://e xac.broadinstitute.org; dbSNP rs397515869). Furthermore, it has been identified by our laboratory in 2 adults (1 male, 1 female) with DCM and did not segregate with disease in either family.

Comment:

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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
Functional characterisation of alpha-galactosidase a mutations as a basis for a new classification system in fabry disease.	Lukas J	PLoS genetics	2013	PMID: 23935525
Fabry disease: 45 novel mutations in the alpha-galactosidase A gene causing the classical phenotype.	Shabbeer J	Molecular genetics and metabolism	2002	PMID: 12175777

Text-mined citations for rs397515869 ...

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 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000169.3(GLA):c.1153A>G (p.Thr385Ala)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs397515869 ...