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NM_000169.3(GLA):c.514T>C (p.Cys172Arg) AND Fabry disease

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jan 16, 2024
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:
RCV003509075.2

Allele description [Variation Report for NM_000169.3(GLA):c.514T>C (p.Cys172Arg)]

NM_000169.3(GLA):c.514T>C (p.Cys172Arg)

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.514T>C (p.Cys172Arg)
HGVS:
  • NC_000023.11:g.101401665A>G
  • NG_007119.1:g.11299T>C
  • NM_000169.3:c.514T>CMANE SELECT
  • NM_001199973.2:c.300+6208A>G
  • NM_001199974.2:c.177+9843A>G
  • NM_001406747.1:c.637T>C
  • NM_001406748.1:c.514T>C
  • NM_001406749.1:c.637T>C
  • NP_000160.1:p.Cys172Arg
  • NP_000160.1:p.Cys172Arg
  • NP_001393676.1:p.Cys213Arg
  • NP_001393677.1:p.Cys172Arg
  • NP_001393678.1:p.Cys213Arg
  • LRG_672t1:c.514T>C
  • LRG_672:g.11299T>C
  • LRG_672p1:p.Cys172Arg
  • NC_000023.10:g.100656653A>G
  • NM_000169.2:c.514T>C
  • NR_164783.1:n.536T>C
  • NR_176252.1:n.536T>C
  • NR_176253.1:n.536T>C
Protein change:
C172R
Molecular consequence:
  • NM_001199973.2:c.300+6208A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001199974.2:c.177+9843A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000169.3:c.514T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406747.1:c.637T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406748.1:c.514T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406749.1:c.637T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NR_164783.1:n.536T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_176252.1:n.536T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_176253.1:n.536T>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
SCV004299642Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Jan 16, 2024) 		germlineclinical testing

PubMed (6)
[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

Skin globotriaosylceramide 3 deposits are specific to Fabry disease with classical mutations and associated with small fibre neuropathy.

Liguori R, Incensi A, de Pasqua S, Mignani R, Fileccia E, Santostefano M, Biagini E, Rapezzi C, Palmieri S, Romani I, Borsini W, Burlina A, Bombardi R, Caprini M, Avoni P, Donadio V.

PLoS One. 2017;12(7):e0180581. doi: 10.1371/journal.pone.0180581.

PubMed [citation]
PMID:
28672034
PMCID:
PMC5495508

Fabry disease: twenty-two novel mutations in the alpha-galactosidase A gene and genotype/phenotype correlations in severely and mildly affected hemizygotes and heterozygotes.

Ashton-Prolla P, Tong B, Shabbeer J, Astrin KH, Eng CM, Desnick RJ.

J Investig Med. 2000 Jul;48(4):227-35.

PubMed [citation]
PMID:
10916280
See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004299642.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 172 of the GLA protein (p.Cys172Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Fabry disease (PMID: 10916280, 15091117, 28672034). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GLA protein function with a positive predictive value of 80%. This variant disrupts the p.Cys172 amino acid residue in GLA. Other variant(s) that disrupt this residue have been observed in individuals with GLA-related conditions (PMID: 10916280, 11322659, 15091117, 23935525), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: Sep 29, 2024