NM_000169.3(GLA):c.782G>T (p.Gly261Val) AND Fabry disease

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Sep 19, 2025
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000780301.8

Allele description [Variation Report for NM_000169.3(GLA):c.782G>T (p.Gly261Val)]

NM_000169.3(GLA):c.782G>T (p.Gly261Val)

Genes:

RPL36A-HNRNPH2:RPL36A-HNRNPH2 readthrough [Gene - HGNC]
GLA:galactosidase alpha [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xq22.1

Genomic location:

Preferred name:

NM_000169.3(GLA):c.782G>T (p.Gly261Val)

HGVS:

NC_000023.11:g.101398804C>A
NG_007119.1:g.14160G>T
NM_000169.3:c.782G>TMANE SELECT
NM_001199973.2:c.300+3347C>A
NM_001199974.2:c.177+6982C>A
NM_001406747.1:c.905G>T
NM_001406748.1:c.782G>T
NP_000160.1:p.Gly261Val
NP_000160.1:p.Gly261Val
NP_001393676.1:p.Gly302Val
NP_001393677.1:p.Gly261Val
LRG_672t1:c.782G>T
LRG_672:g.14160G>T
LRG_672p1:p.Gly261Val
NC_000023.10:g.100653792C>A
NM_000169.2:c.782G>T
NR_164783.1:n.861G>T
NR_176252.1:n.712G>T
NR_176253.1:n.919G>T
p.G261V

Protein change:

G261V

Links:

dbSNP: rs869312401

Molecular consequence:

NM_001199973.2:c.300+3347C>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001199974.2:c.177+6982C>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000169.3:c.782G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406747.1:c.905G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406748.1:c.782G>T - missense variant - [Sequence Ontology: SO:0001583]
NR_164783.1:n.861G>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176252.1:n.712G>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176253.1:n.919G>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

Condition(s)

Name:: Fabry disease
Synonyms:: ALPHA-GALACTOSIDASE A DEFICIENCY; ANDERSON-FABRY DISEASE; CERAMIDE TRIHEXOSIDASE DEFICIENCY; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010526; MedGen: C0002986; Orphanet: 324; OMIM: 301500; Human Phenotype Ontology: HP:0001071

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000917463	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Dec 28, 2018)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 23935525, 27629047, 27532257, 29491734, 28988177 Citation Link,
SCV001571672	CeMIA	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 28988177, 25741868
SCV002054407	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 15, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV006336308	Genomenon, Inc, Genomenon, Inc	criteria provided, single submitter (Genomenon Sequence Variant Interpretation Standards)	Pathogenic (Sep 19, 2025)	germline	curation	PubMed (11) [See all records that cite these PMIDs] 37480128, 29491734, 32023956, 25750198, 27629047, 28988177, 36140787, 38002959, 31770509, 23935525, 27657681 Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	4	not provided	not provided	not provided	not provided	clinical testing, curation
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples.

Walsh R, Thomson KL, Ware JS, Funke BH, Woodley J, McGuire KJ, Mazzarotto F, Blair E, Seller A, Taylor JC, Minikel EV, Exome Aggregation Consortium, MacArthur DG, Farrall M, Cook SA, Watkins H.

Genet Med. 2017 Feb;19(2):192-203. doi: 10.1038/gim.2016.90. Epub 2016 Aug 17.

PubMed [citation]

PMID:: 27532257
PMCID:: PMC5116235

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, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

See all PubMed Citations (13)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000917463.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Variant summary: GLA c.782G>T (p.Gly261Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 178774 control chromosomes (gnomAD). c.782G>T has been reported in the literature in multiple individuals affected with Fabry Disease and hypertrophic cardiomyopathy (Wu_2018, Koulousios_2017, Walsh_2017, Alfadhel_2016, Lukas_2013). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function showed that the variant resulted in an in vitro enzyme activity which was <10% of the wild-type and exhibited lyso-Gb3 levels were above the pathological cut-off (Lukas_2013). Based on the evidence outlined above, the variant was classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From CeMIA, SCV001571672.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	4	not provided	not provided	clinical testing	PubMed (2)

Description

The c.782G>T (p.Gly261Val ) variant, located in exon 5 of the GLA gene, has been previously reported in association with Fabry didease in the literature (PMID: 23935525, 27532257, 27629047, 28988177, 29491734). The variant was identified in four members (1 hemizygous male, 3 heterozygous females) of a family, in which only two (1 male, 1 female) were affected with Fabry disease. Bioinformatic analysis by PolyPhen2 algorithm predicted this mutation as probably damaging. It was not detected amongst the 31360 individuals of the Genome Aggregation Database (gnomAD), indicating that it is not a common variant. Missense variants in the same residue have been previously reported in association with Fabry disease (PMID: 9105656, 15712228). Taking all the above into account and according to ACMG Guidelines (Criteria: PM1, PM2, PM5, PP2, PP3, PP4, PP5) the variant is considered likely pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		4	not provided	not provided	not provided

From Genome-Nilou Lab, SCV002054407.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genomenon, Inc, Genomenon, Inc, SCV006336308.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (11)

Description

GLA c.782G>T is a missense variant that changes the amino acid at residue 261 from Glycine to Valine. This variant has been observed in at least one proband affected with Fabry disease (PMID:37480128;29491734;32023956;25750198;27629047;28988177;36140787;38002959;31770509). The variant was found to segregate with disease in at least one affected family (PMID:29491734;38002959). At least one functional study has demonstrated a substantial alteration in protein function relative to the wild-type (PMID:32023956;23935525;27657681). It is absent or not present at a significant frequency in gnomAD. In silico models agree that this variant is possibly or probably damaging. In conclusion, we classify GLA c.782G>T as a pathogenic variant.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jul 14, 2026

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