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NM_000169.3(GLA):c.820G>C (p.Gly274Arg) AND Fabry disease

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
May 27, 2022
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV001368747.8

Allele description [Variation Report for NM_000169.3(GLA):c.820G>C (p.Gly274Arg)]

NM_000169.3(GLA):c.820G>C (p.Gly274Arg)

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.820G>C (p.Gly274Arg)
HGVS:
  • NC_000023.11:g.101398549C>G
  • NG_007119.1:g.14415G>C
  • NM_000169.3:c.820G>CMANE SELECT
  • NM_001199973.2:c.300+3092C>G
  • NM_001199974.2:c.177+6727C>G
  • NM_001406747.1:c.943G>C
  • NM_001406748.1:c.820G>C
  • NP_000160.1:p.Gly274Arg
  • NP_000160.1:p.Gly274Arg
  • NP_001393676.1:p.Gly315Arg
  • NP_001393677.1:p.Gly274Arg
  • LRG_672t1:c.820G>C
  • LRG_672:g.14415G>C
  • LRG_672p1:p.Gly274Arg
  • NC_000023.10:g.100653537C>G
  • NM_000169.2:c.820G>C
  • NR_164783.1:n.899G>C
  • NR_176252.1:n.750G>C
  • NR_176253.1:n.957G>C
Protein change:
G274R
Links:
dbSNP: rs2147472458
NCBI 1000 Genomes Browser:
rs2147472458
Molecular consequence:
  • NM_001199973.2:c.300+3092C>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001199974.2:c.177+6727C>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000169.3:c.820G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406747.1:c.943G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406748.1:c.820G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NR_164783.1:n.899G>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_176252.1:n.750G>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_176253.1:n.957G>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:
Fabry disease
Synonyms:
Angiokeratoma, diffuse; Anderson-Fabry disease; Hereditary dystopic lipidosis; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0010526; MedGen: C0002986; Orphanet: 324; OMIM: 301500; Human Phenotype Ontology: HP:0001071

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001565155Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Likely pathogenic
(May 27, 2022) 		germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Clinical characteristics and mutation spectrum of GLA in Korean patients with Fabry disease by a nationwide survey: Underdiagnosis of late-onset phenotype.

Choi JH, Lee BH, Heo SH, Kim GH, Kim YM, Kim DS, Ko JM, Sohn YB, Hong YH, Lee DH, Kook H, Lim HH, Kim KH, Kim WS, Hong GR, Kim SH, Park SH, Kim CD, Kim SM, Seo JS, Yoo HW.

Medicine (Baltimore). 2017 Jul;96(29):e7387. doi: 10.1097/MD.0000000000007387.

PubMed [citation]
PMID:
28723748
PMCID:
PMC5521888

A late-onset male Fabry disease patient with somatic mosaicism of a classical GLA mutation: a case report.

Bae EH, Choi JM, Ki CS, Ma SK, Yoo HW, Kim SW.

Ann Palliat Med. 2021 Apr;10(4):4926-4931. doi: 10.21037/apm-19-635. Epub 2020 Sep 27.

PubMed [citation]
PMID:
33040545
See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001565155.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 274 of the GLA protein (p.Gly274Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Fabry disease (PMID: 28723748, 33040545; Invitae). ClinVar contains an entry for this variant (Variation ID: 1059459). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This variant disrupts the p.Gly274 amino acid residue in GLA. Other variant(s) that disrupt this residue have been observed in individuals with GLA-related conditions (PMID: 18057066), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024