NM_000169.3(GLA):c.755G>C (p.Arg252Thr) AND Fabry disease

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Oct 10, 2022
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:: RCV000771419.12

Allele description [Variation Report for NM_000169.3(GLA):c.755G>C (p.Arg252Thr)]

NM_000169.3(GLA):c.755G>C (p.Arg252Thr)

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.755G>C (p.Arg252Thr)

HGVS:

NC_000023.11:g.101398831C>G
NG_007119.1:g.14133G>C
NM_000169.3:c.755G>CMANE SELECT
NM_001199973.2:c.300+3374C>G
NM_001199974.2:c.177+7009C>G
NP_000160.1:p.Arg252Thr
NP_000160.1:p.Arg252Thr
LRG_672t1:c.755G>C
LRG_672:g.14133G>C
LRG_672p1:p.Arg252Thr
NC_000023.10:g.100653819C>G
NM_000169.2:c.755G>C
NR_164783.1:n.834G>C
p.R252T

Protein change:

R252T

Links:

dbSNP: rs147026639

NCBI 1000 Genomes Browser:

rs147026639

Molecular consequence:

NM_001199973.2:c.300+3374C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001199974.2:c.177+7009C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000169.3:c.755G>C - missense variant - [Sequence Ontology: SO:0001583]
NR_164783.1:n.834G>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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000903783	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Apr 10, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001489097	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 10, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23935525, 28492532
SCV002054806	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jul 15, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002081339	Natera, Inc.	no assertion criteria provided	Uncertain significance (Aug 5, 2020)	germline	clinical testing

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

Functional characterisation of alpha-galactosidase a mutations as a basis for a new classification system in fabry disease.

Lukas J, Giese AK, Markoff A, Grittner U, Kolodny E, Mascher H, Lackner KJ, Meyer W, Wree P, Saviouk V, Rolfs A.

PLoS Genet. 2013;9(8):e1003632. doi: 10.1371/journal.pgen.1003632. Epub 2013 Aug 1.

PubMed [citation]

PMID:: 23935525
PMCID:: PMC3731228

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):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (3)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV000903783.1

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV001489097.3

#	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 arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 252 of the GLA protein (p.Arg252Thr). This variant is present in population databases (rs147026639, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of Fabry disease (PMID: 23935525). ClinVar contains an entry for this variant (Variation ID: 222380). 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. Experimental studies have shown that this missense change does not substantially affect GLA function (PMID: 23935525). 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, SCV002054806.1

#	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

From Natera, Inc., SCV002081339.1

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

#	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: Apr 15, 2024

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