NM_000169.3(GLA):c.692A>C (p.Asp231Ala) AND Fabry disease

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Jul 15, 2021
Review status:: criteria provided, conflicting classifications

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:: RCV000701032.12

Allele description [Variation Report for NM_000169.3(GLA):c.692A>C (p.Asp231Ala)]

NM_000169.3(GLA):c.692A>C (p.Asp231Ala)

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.692A>C (p.Asp231Ala)

HGVS:

NC_000023.11:g.101398894T>G
NG_007119.1:g.14070A>C
NM_000169.3:c.692A>CMANE SELECT
NM_001199973.2:c.300+3437T>G
NM_001199974.2:c.177+7072T>G
NM_001406747.1:c.815A>C
NM_001406748.1:c.692A>C
NP_000160.1:p.Asp231Ala
NP_000160.1:p.Asp231Ala
NP_001393676.1:p.Asp272Ala
NP_001393677.1:p.Asp231Ala
LRG_672t1:c.692A>C
LRG_672:g.14070A>C
LRG_672p1:p.Asp231Ala
NC_000023.10:g.100653882T>G
NM_000169.2:c.692A>C
NR_164783.1:n.771A>C
NR_176252.1:n.622A>C
NR_176253.1:n.829A>C

Protein change:

D231A

Links:

dbSNP: rs1569303295

NCBI 1000 Genomes Browser:

rs1569303295

Molecular consequence:

NM_001199973.2:c.300+3437T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001199974.2:c.177+7072T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000169.3:c.692A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406747.1:c.815A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406748.1:c.692A>C - missense variant - [Sequence Ontology: SO:0001583]
NR_164783.1:n.771A>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176252.1:n.622A>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176253.1:n.829A>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

Recent activity

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Gm36774 predicted gene, 36774 [Mus musculus]
Gm36774 predicted gene, 36774 [Mus musculus]
Gene ID:102640791

Gene
Gm36774 AND (alive[prop]) (1)
Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000829814	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (May 7, 2018)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 8863162, 18205205, 19287194, 28492532
SCV002054808	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 15, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000829814

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(May 7, 2018)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV002054808

Genome-Nilou Lab

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jul 15, 2021)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Uneven X inactivation in a female monozygotic twin pair with Fabry disease and discordant expression of a novel mutation in the alpha-galactosidase A gene.

Redonnet-Vernhet I, Ploos van Amstel JK, Jansen RP, Wevers RA, Salvayre R, Levade T.

J Med Genet. 1996 Aug;33(8):682-8.

PubMed [citation]

PMID:: 8863162
PMCID:: PMC1050704

Novel mutations of the GLA gene in Japanese patients with Fabry disease and their functional characterization by active site specific chaperone.

Shimotori M, Maruyama H, Nakamura G, Suyama T, Sakamoto F, Itoh M, Miyabayashi S, Ohnishi T, Sakai N, Wataya-Kaneda M, Kubota M, Takahashi T, Mori T, Tamura K, Kageyama S, Shio N, Maeba T, Yahagi H, Tanaka M, Oka M, Sugiyama H, Sugawara T, et al.

Hum Mutat. 2008 Feb;29(2):331. doi: 10.1002/humu.9520.

PubMed [citation]

PMID:: 18205205

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000829814.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces aspartic acid with alanine at codon 231 of the GLA protein (p.Asp231Ala). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and alanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with GLA-related disease. 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. Three different missense substitutions at this codon (p.Asp231Asn, p.Asp231Val, p.Asp231Gly) have been reported in individuals affected with Fabry disease (PMID: 8863162, 18205205, 19287194). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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

From Genome-Nilou Lab, SCV002054808.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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