NM_000169.3(GLA):c.901C>G (p.Arg301Gly) AND Cardiovascular phenotype

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Apr 17, 2023
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:: RCV003298170.3

Allele description [Variation Report for NM_000169.3(GLA):c.901C>G (p.Arg301Gly)]

NM_000169.3(GLA):c.901C>G (p.Arg301Gly)

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.901C>G (p.Arg301Gly)

HGVS:

NC_000023.11:g.101398468G>C
NG_007119.1:g.14496C>G
NM_000169.3:c.901C>GMANE SELECT
NM_001199973.2:c.300+3011G>C
NM_001199974.2:c.177+6646G>C
NP_000160.1:p.Arg301Gly
NP_000160.1:p.Arg301Gly
LRG_672t1:c.901C>G
LRG_672:g.14496C>G
LRG_672p1:p.Arg301Gly
NC_000023.10:g.100653456G>C
NM_000169.2:c.901C>G
NR_164783.1:n.980C>G

Protein change:

R301G

Links:

dbSNP: rs398123224

NCBI 1000 Genomes Browser:

rs398123224

Molecular consequence:

NM_001199973.2:c.300+3011G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001199974.2:c.177+6646G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000169.3:c.901C>G - missense variant - [Sequence Ontology: SO:0001583]
NR_164783.1:n.980C>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Cardiovascular phenotype
Identifiers:: MedGen: CN230736

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003997144	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Apr 17, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 12175777, 21700093, 23935525, 26298600, 27657681, 30085001, 35548424, 36292965 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003997144

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Apr 17, 2023)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Fabry disease: 45 novel mutations in the alpha-galactosidase A gene causing the classical phenotype.

Shabbeer J, Yasuda M, Luca E, Desnick RJ.

Mol Genet Metab. 2002 May;76(1):23-30.

PubMed [citation]

PMID:: 12175777

Exercise-induced left ventricular outflow tract obstruction in symptomatic patients with Anderson-Fabry disease.

Calcagnino M, O'Mahony C, Coats C, Cardona M, Garcia A, Janagarajan K, Mehta A, Hughes D, Murphy E, Lachmann R, Elliott PM.

J Am Coll Cardiol. 2011 Jun 28;58(1):88-9. doi: 10.1016/j.jacc.2011.03.020. No abstract available.

PubMed [citation]

PMID:: 21700093

See all PubMed Citations (8)

Details of each submission

From Ambry Genetics, SCV003997144.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

The p.R301G pathogenic mutation (also known as c.901C>G), located in coding exon 6 of the GLA gene, results from a C to G substitution at nucleotide position 901. The arginine at codon 301 is replaced by glycine, an amino acid with dissimilar properties. This alteration has been reported in numerous individuals with Fabry disease, having low enzyme activity observed (Shabbeer J et al. Mol Genet Metab, 2002 May;76:23-30; Calcagnino M et al. J Am Coll Cardiol, 2011 Jun;58:88-9; Romani I et al. J Stroke Cerebrovasc Dis, 2015 Nov;24:2588-95; Esposito R et al. Eur Heart J Cardiovasc Imaging, 2019 Apr;20:438-445; Citro R et al. Front Cardiovasc Med, 2022 Apr;9:838200; Di Risi T et al. Int J Mol Sci, 2022 Oct;23:[ePub ahead of print]). Another alteration at the same codon, p.R301Q (c.902G>A), has been detected in individuals with Fabry disease, who had reduced enzyme activity (Sakuraba H et al. Am J Hum Genet. 1990;47:784-789; Shin SH et al Biochem. Biophys. Res. Commun. 2007 Jul;359(1):168-73; Sawada K et al. Clin. Nephrol. 1996 May;45:289-294). In vitro studies showed this alteration impacts protein function (Lukas J et al. PLoS Genet, 2013 Aug;9:e1003632; Benjamin ER et al. Genet Med, 2017 Apr;19:430-438). 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 BayesDel in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jul 15, 2024

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