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NM_000169.3(GLA):c.281G>A (p.Cys94Tyr) AND Fabry disease

Germline classification:
Pathogenic (1 submission)
Last evaluated:
May 19, 2021
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:
RCV001854374.14

Allele description [Variation Report for NM_000169.3(GLA):c.281G>A (p.Cys94Tyr)]

NM_000169.3(GLA):c.281G>A (p.Cys94Tyr)

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.281G>A (p.Cys94Tyr)
HGVS:
  • NC_000023.11:g.101403899C>T
  • NG_007119.1:g.9065G>A
  • NG_016327.1:g.697C>T
  • NM_000169.3:c.281G>AMANE SELECT
  • NM_001199973.2:c.301-8037C>T
  • NM_001199974.2:c.178-8037C>T
  • NM_001406747.1:c.404G>A
  • NM_001406748.1:c.281G>A
  • NM_001406749.1:c.404G>A
  • NP_000160.1:p.Cys94Tyr
  • NP_000160.1:p.Cys94Tyr
  • NP_001393676.1:p.Cys135Tyr
  • NP_001393677.1:p.Cys94Tyr
  • NP_001393678.1:p.Cys135Tyr
  • LRG_672t1:c.281G>A
  • LRG_672:g.9065G>A
  • LRG_672p1:p.Cys94Tyr
  • NC_000023.10:g.100658887C>T
  • NM_000169.2:c.281G>A
  • NR_164783.1:n.303G>A
  • NR_176252.1:n.303G>A
  • NR_176253.1:n.303G>A
  • P06280:p.Cys94Tyr
  • p.C94Y
Protein change:
C135Y
Links:
UniProtKB: P06280#VAR_012380; dbSNP: rs113173389
NCBI 1000 Genomes Browser:
rs113173389
Molecular consequence:
  • NM_001199973.2:c.301-8037C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001199974.2:c.178-8037C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000169.3:c.281G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406747.1:c.404G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406748.1:c.281G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406749.1:c.404G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NR_164783.1:n.303G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_176252.1:n.303G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_176253.1:n.303G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
Functional consequence:
effect on protein activity [Variation Ontology: 0053]

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

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV002176024Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(May 19, 2021)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Summary from all submissions

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

Citations

PubMed

Functional evaluation of a novel GLA causative mutation in Fabry disease.

Li P, Zhang L, Xiong Q, Wang Z, Cui X, Zhou YA, Wang Y, Xiao H, Wu C.

Mol Genet Genomic Med. 2019 Sep;7(9):e864. doi: 10.1002/mgg3.864. Epub 2019 Jul 18.

PubMed [citation]
PMID:
31321922
PMCID:
PMC6732343

Fabry disease: 20 novel GLA mutations in 35 families.

Blaydon D, Hill J, Winchester B.

Hum Mutat. 2001 Nov;18(5):459.

PubMed [citation]
PMID:
11668641
See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002176024.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys94 amino acid residue in GLA. Other variant(s) that disrupt this residue have been observed in individuals with GLA-related conditions (PMID: 31321922, 9100224, 11668641, Invitae), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this variant affects GLA protein function (PMID: 26415523). This variant has been observed in individual(s) with X-linked Fabry disease (PMID: 9100224, Invitae). ClinVar contains an entry for this variant (Variation ID: 92549). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with tyrosine at codon 94 of the GLA protein (p.Cys94Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine.

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

Last Updated: Nov 3, 2024