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NM_000169.3(GLA):c.274G>C (p.Asp92His) AND Fabry disease

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jul 22, 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:
RCV001553582.2

Allele description [Variation Report for NM_000169.3(GLA):c.274G>C (p.Asp92His)]

NM_000169.3(GLA):c.274G>C (p.Asp92His)

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.274G>C (p.Asp92His)
HGVS:
  • NC_000023.11:g.101403906C>G
  • NG_007119.1:g.9058G>C
  • NG_016327.1:g.704C>G
  • NM_000169.3:c.274G>CMANE SELECT
  • NM_001199973.2:c.301-8030C>G
  • NM_001199974.2:c.178-8030C>G
  • NM_001406747.1:c.397G>C
  • NM_001406748.1:c.274G>C
  • NM_001406749.1:c.397G>C
  • NP_000160.1:p.Asp92His
  • NP_000160.1:p.Asp92His
  • NP_001393676.1:p.Asp133His
  • NP_001393677.1:p.Asp92His
  • NP_001393678.1:p.Asp133His
  • LRG_672t1:c.274G>C
  • LRG_672:g.9058G>C
  • LRG_672p1:p.Asp92His
  • NC_000023.10:g.100658894C>G
  • NM_000169.2:c.274G>C
  • NR_164783.1:n.296G>C
  • NR_176252.1:n.296G>C
  • NR_176253.1:n.296G>C
Protein change:
D133H
Links:
dbSNP: rs886041315
NCBI 1000 Genomes Browser:
rs886041315
Molecular consequence:
  • NM_001199973.2:c.301-8030C>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001199974.2:c.178-8030C>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000169.3:c.274G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406747.1:c.397G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406748.1:c.274G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406749.1:c.397G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NR_164783.1:n.296G>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_176252.1:n.296G>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_176253.1:n.296G>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
SCV001774485Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Pathogenic
(Jul 22, 2021) 		germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Fabry disease: fourteen alpha-galactosidase A mutations in unrelated families from the United Kingdom and other European countries.

Davies JP, Eng CM, Hill JA, Malcolm S, MacDermot K, Winchester B, Desnick RJ.

Eur J Hum Genet. 1996;4(4):219-24.

PubMed [citation]
PMID:
8875188

Structural basis of Fabry disease.

Garman SC, Garboczi DN.

Mol Genet Metab. 2002 Sep-Oct;77(1-2):3-11. Review.

PubMed [citation]
PMID:
12359124
See all PubMed Citations (7)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001774485.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

Variant summary: GLA c.274G>C (p.Asp92His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183388 control chromosomes. c.274G>C has been reported in the literature in multiple individuals affected with Fabry Disease (example, Davies_1996, Germain_2015, Phyu_2018, McCreary_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (example, Germain_2015). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.

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

Last Updated: Sep 16, 2024