VCV000222387.9 - ClinVar

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

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic/Likely pathogenic
Pathogenic (3); Likely pathogenic (2)

5 out of 5 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 222387 Accession: VCV000222387.9

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq22.1 X: 101398804 (GRCh38) [ NCBI UCSC ] X: 100653792 (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	Jun 2, 2019	Apr 25, 2026	Feb 11, 2026

HGVS

Nucleotide	Protein	Molecular consequence
NM_000169.3:c.782G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000160.1:p.Gly261Val	missense
NM_001199973.2:c.300+3347C>A		intron variant
NM_001199974.2:c.177+6982C>A		intron variant
NM_001406747.1:c.905G>T	NP_001393676.1:p.Gly302Val	missense
NM_001406748.1:c.782G>T	NP_001393677.1:p.Gly261Val	missense
NR_164783.1:n.861G>T		non-coding transcript variant
NR_176252.1:n.712G>T		non-coding transcript variant
NR_176253.1:n.919G>T		non-coding transcript variant
NC_000023.11:g.101398804C>A
NC_000023.10:g.100653792C>A
NG_007119.1:g.14160G>T
LRG_672:g.14160G>T
LRG_672t1:c.782G>T	LRG_672p1:p.Gly261Val

... more HGVS ... less HGVS

Protein change

G261V, G302V

Other names

Canonical SPDI

NC_000023.11:101398803:C:A

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: CA352632 dbSNP: rs869312401 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	6	2240
RPL36A-HNRNPH2	-	-	-	GRCh38 GRCh37	-	2321

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 (4)	criteria provided, multiple submitters, no conflicts	Sep 19, 2025	RCV000780301.8
Cardiovascular phenotype	Pathogenic (1)	criteria provided, single submitter	Feb 11, 2026	RCV006649981.1

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.	Expand all rows Collapse all rows 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 (Jul 15, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Fabry disease	Genome-Nilou Lab Accession: SCV002054407.1 First in ClinVar: Jan 12, 2022 Last updated: Jan 12, 2022	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: no Observation 1 Collection method: clinical testing Allele origin: germline Affected status: no

Likely pathogenic (-) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Fabry disease	CeMIA Accession: SCV001571672.3 First in ClinVar: Apr 24, 2021 Last updated: Apr 13, 2025	Publications: PubMed (1) PubMed: 28988177 Comment: show 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. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 4 Sex: mixed Testing laboratory: CeMIA

Pathogenic (Feb 11, 2026) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cardiovascular phenotype	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute Accession: SCV007541423.1 First in ClinVar: Apr 25, 2026 Last updated: Apr 25, 2026	Comment: show PS3_supp, PS4_mod, PM2, PM5, PP1_strong, PP2, PP4 (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (Dec 28, 2018) C Contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Fabry disease	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000917463.1 First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019	Publications: PubMed (5) PubMed: 23935525‚ 27532257‚ 27629047‚ 28988177‚ 29491734 Comment: show 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. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Sep 19, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Genomenon Sequence Variant Interpretation Standards)	Fabry disease	Genomenon, Inc, Genomenon, Inc Accession: SCV006336308.1 First in ClinVar: Sep 27, 2025 Last updated: Sep 27, 2025	Publications: PubMed (11) PubMed: 23935525‚ 25750198‚ 27629047‚ 27657681‚ 28988177‚ 29491734‚ 31770509‚ 32023956‚ 36140787‚ 37480128‚ 38002959 Comment: show 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. (less) Observation: 1 Collection method: curation Allele origin: germline Affected status: yes Observation 1 Collection method: curation Allele origin: germline Affected status: yes

Comment:

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.

Comment:

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.

Comment:

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.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Genotype-Phenotype Correlations in 293 Russian Patients with Causal Fabry Disease Variants.	Savostyanov K	Genes	2023	PMID: 38002959
Low skeletal muscle mass as an early sign in children with fabry disease.	Lu Z	Orphanet journal of rare diseases	2023	PMID: 37480128
The Benefits of Family Screening in Rare Diseases: Genetic Testing Reveals 165 New Cases of Fabry Disease among At-Risk Family Members of 83 Index Patients.	Moiseev S	Genes	2022	PMID: 36140787
Assessment of Gene Variant Amenability for Pharmacological Chaperone Therapy with 1-Deoxygalactonojirimycin in Fabry Disease.	Lukas J	International journal of molecular sciences	2020	PMID: 32023956
α-Galactosidase A/lysoGb3 ratio as a potential marker for Fabry disease in females.	Baydakova GV	Clinica chimica acta; international journal of clinical chemistry	2020	PMID: 31770509
Identification of a Missense Mutation in the α-galactosidase A Gene in a Chinese Family with Fabry Disease.	Wu Y	Current genomics	2018	PMID: 29491734
Fabry disease due to D313Y and novel GLA mutations.	Koulousios K	BMJ open	2017	PMID: 28988177
The validation of pharmacogenetics for the identification of Fabry patients to be treated with migalastat.	Benjamin ER	Genetics in medicine : official journal of the American College of Medical Genetics	2017	PMID: 27657681
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
Thirteen year retrospective review of the spectrum of inborn errors of metabolism presenting in a tertiary center in Saudi Arabia.	Alfadhel M	Orphanet journal of rare diseases	2016	PMID: 27629047
Normal left-atrial structure and function despite concentric left-ventricular remodelling in a cohort of patients with Anderson-Fabry disease.	Putko BN	European heart journal. Cardiovascular Imaging	2015	PMID: 25750198
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
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Text-mined citations for rs869312401 ...

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 Jun 14, 2026