NM_000169.3(GLA):c.1231G>A (p.Gly411Ser) AND Fabry disease

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Dec 20, 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:: RCV003838118.2

Allele description [Variation Report for NM_000169.3(GLA):c.1231G>A (p.Gly411Ser)]

NM_000169.3(GLA):c.1231G>A (p.Gly411Ser)

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.1231G>A (p.Gly411Ser)

HGVS:

NC_000023.11:g.101397868C>T
NG_007119.1:g.15096G>A
NM_000169.3:c.1231G>AMANE SELECT
NM_001199973.2:c.300+2411C>T
NM_001199974.2:c.177+6046C>T
NM_001406747.1:c.1354G>A
NP_000160.1:p.Gly411Ser
NP_000160.1:p.Gly411Ser
NP_001393676.1:p.Gly452Ser
LRG_672t1:c.1231G>A
LRG_672:g.15096G>A
LRG_672p1:p.Gly411Ser
NC_000023.10:g.100652856C>T
NM_000169.2:c.1231G>A
NR_164783.1:n.1310G>A
NR_176252.1:n.1161G>A
NR_176253.1:n.1368G>A

Protein change:

G411S

Molecular consequence:

NM_001199973.2:c.300+2411C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001199974.2:c.177+6046C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000169.3:c.1231G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406747.1:c.1354G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_164783.1:n.1310G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176252.1:n.1161G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176253.1:n.1368G>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
SCV004631074	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 20, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31956509, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004631074

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 20, 2023)

germline

clinical testing

PubMed (2)
[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

Newborn screening for Fabry disease in the western region of Japan.

Sawada T, Kido J, Yoshida S, Sugawara K, Momosaki K, Inoue T, Tajima G, Sawada H, Mastumoto S, Endo F, Hirose S, Nakamura K.

Mol Genet Metab Rep. 2020 Mar;22:100562. doi: 10.1016/j.ymgmr.2019.100562.

PubMed [citation]

PMID:: 31956509
PMCID:: PMC6961758

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004631074.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 411 of the GLA protein (p.Gly411Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Fabry disease (PMID: 31956509; Invitae). 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 not expected to disrupt GLA protein function with a negative predictive value of 80%. 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

Last Updated: Sep 29, 2024

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