VCV000092574.18 - ClinVar

NM_000169.3(GLA):c.974G>A (p.Gly325Asp)

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.974G>A (p.Gly325Asp)

Variation ID: 92574 Accession: VCV000092574.18

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq22.1 X: 101398395 (GRCh38) [ NCBI UCSC ] X: 100653383 (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	Feb 24, 2015	Jun 23, 2024	Dec 1, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000169.3:c.974G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000160.1:p.Gly325Asp	missense
NM_001199973.2:c.300+2938C>T		intron variant
NM_001199974.2:c.177+6573C>T		intron variant
NM_001406747.1:c.1097G>A	NP_001393676.1:p.Gly366Asp	missense
NM_001406748.1:c.974G>A	NP_001393677.1:p.Gly325Asp	missense
NR_164783.1:n.1053G>A		non-coding transcript variant
NR_176252.1:n.904G>A		non-coding transcript variant
NR_176253.1:n.1111G>A		non-coding transcript variant
NC_000023.11:g.101398395C>T
NC_000023.10:g.100653383C>T
NG_007119.1:g.14569G>A
LRG_672:g.14569G>A
LRG_672t1:c.974G>A	LRG_672p1:p.Gly325Asp

... more HGVS ... less HGVS

Protein change

G366D

Other names

p.G325D:GGC>GAC

Canonical SPDI

NC_000023.11:101398394: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: CA022237 dbSNP: rs398123228 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	Dec 1, 2023	RCV000078306.23
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Dec 10, 2019	RCV000157881.17

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 (Feb 08, 2013)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000110146.8 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=GLA Sex: mixed
Pathogenic (Nov 28, 2012)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000207812.10 First in ClinVar: Feb 24, 2015 Last updated: Dec 15, 2018	Comment: The Gly325Asp mutation in the GLA gene has been reported in association with Fabry disease (Schafer E et al., 2005; Wu X et al., 2011). … (more) The Gly325Asp mutation in the GLA gene has been reported in association with Fabry disease (Schafer E et al., 2005; Wu X et al., 2011). Mutations affecting nearby residues (Asp322Gly, Gln327Glu, Gln327Lys) have also been reported in association with Fabry disease, further supporting the functional importance of this region of the protein. Furthermore, the NHLBI ESP Exome Variant Server reports Gly325Asp was not observed in approximately 6,500 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations.In summary, Gly325Asp in the GLA gene is interpreted as a disease-causing mutation. The variant is found in HCM panel(s). (less)
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: SCV002054390.1 First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022
Likely pathogenic (Dec 01, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Fabry disease Affected status: yes Allele origin: maternal	Precision Medicine Center, Zhengzhou University Accession: SCV004218459.1 First in ClinVar: Jun 23, 2024 Last updated: Jun 23, 2024	Publications: PubMed (2) PubMed: 15776423‚ 25741868 Comment: PM2_p,PP3_strong,PP4 Sex: male
Pathogenic (Dec 10, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002024279.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (May 21, 2017)	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: SCV000622197.4 First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024	Publications: PubMed (3) PubMed: 15713906‚ 19387866‚ 15776423 Comment: Experimental studies have shown that this missense greatly reduces GLA enzymatic activity (PMID: 15713906, 19387866 , 21598360). For these reasons, this variant has been classified … (more) Experimental studies have shown that this missense greatly reduces GLA enzymatic activity (PMID: 15713906, 19387866 , 21598360). For these reasons, this variant has been classified as Pathogenic. This variant has been reported in individuals affected with Fabry disease (PMID: 15713906, 15776423, Invitae). ClinVar contains an entry for this variant (Variation ID: 92574) This variant is not present in population databases (rs398123228, ExAC no frequency). This sequence change replaces glycine with aspartic acid at codon 325 of the GLA protein (p.Gly325Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. (less)

Comment:

The Gly325Asp mutation in the GLA gene has been reported in association with Fabry disease (Schafer E et al., 2005; Wu X et al., 2011). Mutations affecting nearby residues (Asp322Gly, Gln327Glu, Gln327Lys) have also been reported in association with Fabry disease, further supporting the functional importance of this region of the protein. Furthermore, the NHLBI ESP Exome Variant Server reports Gly325Asp was not observed in approximately 6,500 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations.In summary, Gly325Asp in the GLA gene is interpreted as a disease-causing mutation. The variant is found in HCM panel(s).

Comment:

Experimental studies have shown that this missense greatly reduces GLA enzymatic activity (PMID: 15713906, 19387866 , 21598360). For these reasons, this variant has been classified as Pathogenic. This variant has been reported in individuals affected with Fabry disease (PMID: 15713906, 15776423, Invitae). ClinVar contains an entry for this variant (Variation ID: 92574) This variant is not present in population databases (rs398123228, ExAC no frequency). This sequence change replaces glycine with aspartic acid at codon 325 of the GLA protein (p.Gly325Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid.

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
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.	Richards S	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25741868
The pharmacological chaperone 1-deoxygalactonojirimycin increases alpha-galactosidase A levels in Fabry patient cell lines.	Benjamin ER	Journal of inherited metabolic disease	2009	PMID: 19387866
Thirty-four novel mutations of the GLA gene in 121 patients with Fabry disease.	Schäfer E	Human mutation	2005	PMID: 15776423
Pediatric Fabry disease.	Ries M	Pediatrics	2005	PMID: 15713906
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GLA	-	-	-	-

Text-mined citations for rs398123228 ...

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 10, 2024

ClinVar Genomic variation as it relates to human health

NM_000169.3(GLA):c.974G>A (p.Gly325Asp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs398123228 ...