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NM_000169.3(GLA):c.335G>A (p.Arg112His) AND Cardiovascular phenotype

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Nov 9, 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:
RCV002321693.3

Allele description

NM_000169.3(GLA):c.335G>A (p.Arg112His)

Genes:
HNRNPH2:heterogeneous nuclear ribonucleoprotein H2 [Gene - OMIM - HGNC]
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.335G>A (p.Arg112His)
HGVS:
  • NC_000023.11:g.101403845C>T
  • NG_007119.1:g.9119G>A
  • NG_016327.1:g.643C>T
  • NM_000169.3:c.335G>AMANE SELECT
  • NM_001199973.2:c.301-8091C>T
  • NM_001199974.2:c.178-8091C>T
  • NP_000160.1:p.Arg112His
  • NP_000160.1:p.Arg112His
  • LRG_672t1:c.335G>A
  • LRG_672:g.9119G>A
  • LRG_672p1:p.Arg112His
  • NC_000023.10:g.100658833C>T
  • NM_000169.2(GLA):c.335G>A
  • NM_000169.2:c.335G>A
  • NR_164783.1:n.357G>A
  • P06280:p.Arg112His
  • p.R112H
Protein change:
R112H
Links:
UniProtKB: P06280#VAR_000448; dbSNP: rs372966991
NCBI 1000 Genomes Browser:
rs372966991
Molecular consequence:
  • NM_001199973.2:c.301-8091C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001199974.2:c.178-8091C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000169.3:c.335G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NR_164783.1:n.357G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
Functional consequence:
effect on protein activity [Variation Ontology: 0053]
Observations:
1

Condition(s)

Name:
Cardiovascular phenotype
Identifiers:
MedGen: CN230736

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV002606289Ambry Genetics
criteria provided, single submitter

(Ambry General Variant Classification Scheme_2022)
Pathogenic
(Nov 9, 2021)
germlineclinical testing

PubMed (13)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing

Citations

PubMed

Screening for pharmacological chaperones in Fabry disease.

Shin SH, Murray GJ, Kluepfel-Stahl S, Cooney AM, Quirk JM, Schiffmann R, Brady RO, Kaneski CR.

Biochem Biophys Res Commun. 2007 Jul 20;359(1):168-73. Epub 2007 May 22.

PubMed [citation]
PMID:
17532296
PMCID:
PMC2729584

Mutant alpha-galactosidase A enzymes identified in Fabry disease patients with residual enzyme activity: biochemical characterization and restoration of normal intracellular processing by 1-deoxygalactonojirimycin.

Ishii S, Chang HH, Kawasaki K, Yasuda K, Wu HL, Garman SC, Fan JQ.

Biochem J. 2007 Sep 1;406(2):285-95.

PubMed [citation]
PMID:
17555407
PMCID:
PMC1948963
See all PubMed Citations (13)

Details of each submission

From Ambry Genetics, SCV002606289.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (13)

Description

The p.R112H pathogenic mutation (also known as c.335G>A), located in coding exon 2 of the GLA gene, results from a G to A substitution at nucleotide position 335. The arginine at codon 112 is replaced by histidine, an amino acid with highly similar properties. This alteration has been detected in many individuals with Fabry disease and is described as being associated with later onset disease (Weidemann F et al. Mol. Genet. Metab., 2019 Feb;126:169-182; Sakuraba H et al. Mol Genet Metab Rep, 2018 Dec;17:73-79; Natarajan P et al. Sci Transl Med, 2016 11;8:364ra151; Riera C et al. Proteins, 2015 Jan;83:91-104; Smid BE et al. Clin. Genet., 2015 Aug;88:161-6; Nishida M et al. Eur. J. Pediatr., 2014 Aug;173:1111-4; Sechi A et al. BMC Cardiovasc Disord, 2014 Jul;14:86). In addition, several functional studies have shown reduced alpha-galactosidase protein function (Ishii S et al. Biochem. J., 2007 Sep;406:285-95; Lukas J et al. PLoS Genet., 2013 Aug;9:e1003632; Saito S et al. PLoS ONE, 2013 Dec;8:e84267; Shimotori M et al. Hum. Mutat., 2008 Feb;29:331; Shin SH et al. Biochem. Biophys. Res. Commun., 2007 Jul;359:168-73). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown1not providednot provided1not providednot providednot provided

Last Updated: Apr 15, 2024