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NM_000169.3(GLA):c.605G>A (p.Cys202Tyr) AND Fabry disease

Germline classification:
Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:
Sep 29, 2022
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:
RCV000359005.11

Allele description [Variation Report for NM_000169.3(GLA):c.605G>A (p.Cys202Tyr)]

NM_000169.3(GLA):c.605G>A (p.Cys202Tyr)

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.605G>A (p.Cys202Tyr)
HGVS:
  • NC_000023.11:g.101400700C>T
  • NG_007119.1:g.12264G>A
  • NM_000169.3:c.605G>AMANE SELECT
  • NM_001199973.2:c.300+5243C>T
  • NM_001199974.2:c.177+8878C>T
  • NM_001406747.1:c.728G>A
  • NM_001406748.1:c.605G>A
  • NP_000160.1:p.Cys202Tyr
  • NP_000160.1:p.Cys202Tyr
  • NP_001393676.1:p.Cys243Tyr
  • NP_001393677.1:p.Cys202Tyr
  • LRG_672t1:c.605G>A
  • LRG_672:g.12264G>A
  • LRG_672p1:p.Cys202Tyr
  • NC_000023.10:g.100655688C>T
  • NM_000169.2:c.605G>A
  • NR_164783.1:n.627G>A
  • NR_176253.1:n.742G>A
  • P06280:p.Cys202Tyr
  • p.C202Y
Protein change:
C202Y
Links:
UniProtKB: P06280#VAR_012398; dbSNP: rs869312344
NCBI 1000 Genomes Browser:
rs869312344
Molecular consequence:
  • NM_001199973.2:c.300+5243C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001199974.2:c.177+8878C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000169.3:c.605G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406747.1:c.728G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406748.1:c.605G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NR_164783.1:n.627G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_176253.1:n.742G>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
SCV000748693Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Sep 29, 2022)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV002054429Genome-Nilou Lab
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Jul 15, 2021)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

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

Citations

PubMed

Fabry disease: identification of novel alpha-galactosidase A mutations and molecular carrier detection by use of fluorescent chemical cleavage of mismatches.

Germain DP, Poenaru L.

Biochem Biophys Res Commun. 1999 Apr 21;257(3):708-13.

PubMed [citation]
PMID:
10208848

Functional and Clinical Consequences of Novel α-Galactosidase A Mutations in Fabry Disease.

Lukas J, Scalia S, Eichler S, Pockrandt AM, Dehn N, Cozma C, Giese AK, Rolfs A.

Hum Mutat. 2016 Jan;37(1):43-51. doi: 10.1002/humu.22910. Epub 2015 Oct 27.

PubMed [citation]
PMID:
26415523
See all PubMed Citations (7)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000748693.4

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

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys202 amino acid residue in GLA. Other variant(s) that disrupt this residue have been observed in individuals with GLA-related conditions (PMID: 10208848), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that this missense change affects GLA function (PMID: 26415523). 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. ClinVar contains an entry for this variant (Variation ID: 222314). This missense change has been observed in individual(s) with Fabry disease (PMID: 9100224, 19387866, 23935525; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 202 of the GLA protein (p.Cys202Tyr).

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

From Genome-Nilou Lab, SCV002054429.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenonot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024