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NM_000169.3(GLA):c.1018T>C (p.Trp340Arg) AND Fabry disease

Germline classification:
Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:
Jul 15, 2021
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:
RCV001244524.11

Allele description [Variation Report for NM_000169.3(GLA):c.1018T>C (p.Trp340Arg)]

NM_000169.3(GLA):c.1018T>C (p.Trp340Arg)

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.1018T>C (p.Trp340Arg)
HGVS:
  • NC_000023.11:g.101398081A>G
  • NG_007119.1:g.14883T>C
  • NM_000169.3:c.1018T>CMANE SELECT
  • NM_001199973.2:c.300+2624A>G
  • NM_001199974.2:c.177+6259A>G
  • NM_001406747.1:c.1141T>C
  • NP_000160.1:p.Trp340Arg
  • NP_000160.1:p.Trp340Arg
  • NP_001393676.1:p.Trp381Arg
  • LRG_672t1:c.1018T>C
  • LRG_672:g.14883T>C
  • LRG_672p1:p.Trp340Arg
  • NC_000023.10:g.100653069A>G
  • NM_000169.2:c.1018T>C
  • NR_164783.1:n.1097T>C
  • NR_176252.1:n.948T>C
  • NR_176253.1:n.1155T>C
Protein change:
W340R
Links:
dbSNP: rs1555984869
NCBI 1000 Genomes Browser:
rs1555984869
Molecular consequence:
  • NM_001199973.2:c.300+2624A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001199974.2:c.177+6259A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000169.3:c.1018T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406747.1:c.1141T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NR_164783.1:n.1097T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_176252.1:n.948T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_176253.1:n.1155T>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

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001417750Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Feb 13, 2020)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV002054386Genome-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

Frequency of de novo mutations in Japanese patients with Fabry disease.

Kobayashi M, Ohashi T, Iizuka S, Kaneshiro E, Higuchi T, Eto Y, Ida H.

Mol Genet Metab Rep. 2014;1:283-287.

PubMed [citation]
PMID:
27896102
PMCID:
PMC5121308

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818
See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001417750.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This variant has been observed in an individual affected with Fabry disease (Invitae). ClinVar contains an entry for this variant (Variation ID: 546086). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Trp340 amino acid residue in GLA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27896102). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant is not present in population databases (ExAC no frequency). This sequence change replaces tryptophan with arginine at codon 340 of the GLA protein (p.Trp340Arg). The tryptophan residue is highly conserved and there is a moderate physicochemical difference between tryptophan and arginine.

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

From Genome-Nilou Lab, SCV002054386.1

#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