NM_000169.3(GLA):c.1016T>A (p.Val339Glu) AND Fabry disease

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Nov 8, 2022
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:: RCV003622156.2

Allele description [Variation Report for NM_000169.3(GLA):c.1016T>A (p.Val339Glu)]

NM_000169.3(GLA):c.1016T>A (p.Val339Glu)

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.1016T>A (p.Val339Glu)

HGVS:

NC_000023.11:g.101398083A>T
NG_007119.1:g.14881T>A
NM_000169.3:c.1016T>AMANE SELECT
NM_001199973.2:c.300+2626A>T
NM_001199974.2:c.177+6261A>T
NM_001406747.1:c.1139T>A
NP_000160.1:p.Val339Glu
NP_000160.1:p.Val339Glu
NP_001393676.1:p.Val380Glu
LRG_672t1:c.1016T>A
LRG_672:g.14881T>A
LRG_672p1:p.Val339Glu
NC_000023.10:g.100653071A>T
NM_000169.2:c.1016T>A
NR_164783.1:n.1095T>A
NR_176252.1:n.946T>A
NR_176253.1:n.1153T>A

Protein change:

V339E

Molecular consequence:

NM_001199973.2:c.300+2626A>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001199974.2:c.177+6261A>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000169.3:c.1016T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406747.1:c.1139T>A - missense variant - [Sequence Ontology: SO:0001583]
NR_164783.1:n.1095T>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176252.1:n.946T>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176253.1:n.1153T>A - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004535506	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 8, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 31860127, 30988410, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004535506

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Nov 8, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

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

Diagnostic strategy for females suspected of Fabry disease.

Balendran S, Oliva P, Sansen S, Mechtler TP, Streubel B, Cobos PN, Lukacs Z, Kasper DC.

Clin Genet. 2020 Apr;97(4):655-660. doi: 10.1111/cge.13694. Epub 2020 Jan 7.

PubMed [citation]

PMID:: 31860127

Mutation spectrum of α-Galactosidase gene in Japanese patients with Fabry disease.

Kobayashi M, Ohashi T, Kaneshiro E, Higuchi T, Ida H.

J Hum Genet. 2019 Jul;64(7):695-699. doi: 10.1038/s10038-019-0599-z. Epub 2019 Apr 15.

PubMed [citation]

PMID:: 30988410

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004535506.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

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. This variant disrupts the p.Val339 amino acid residue in GLA. Other variant(s) that disrupt this residue have been observed in individuals with GLA-related conditions (PMID: 31860127), which suggests that this may be a clinically significant amino acid residue. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GLA protein function. This missense change has been observed in individual(s) with Fabry disease (PMID: 30988410). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 339 of the GLA protein (p.Val339Glu).

#	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: Sep 29, 2024

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