NM_000169.3(GLA):c.85G>T (p.Ala29Ser) AND Fabry disease

Germline classification:: Uncertain significance (4 submissions)
Last evaluated:: Mar 15, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001187973.14

Allele description [Variation Report for NM_000169.3(GLA):c.85G>T (p.Ala29Ser)]

NM_000169.3(GLA):c.85G>T (p.Ala29Ser)

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.85G>T (p.Ala29Ser)

HGVS:

NC_000023.11:g.101407819C>A
NG_007119.1:g.5145G>T
NG_016327.1:g.4617C>A
NM_000169.3:c.85G>TMANE SELECT
NM_001199973.2:c.301-4117C>A
NM_001199974.2:c.178-4117C>A
NM_001406747.1:c.85G>T
NM_001406748.1:c.85G>T
NM_001406749.1:c.85G>T
NP_000160.1:p.Ala29Ser
NP_000160.1:p.Ala29Ser
NP_001393676.1:p.Ala29Ser
NP_001393677.1:p.Ala29Ser
NP_001393678.1:p.Ala29Ser
LRG_672t1:c.85G>T
LRG_672:g.5145G>T
LRG_672p1:p.Ala29Ser
NC_000023.10:g.100662807C>A
NM_000169.2:c.85G>T
NR_164783.1:n.107G>T
NR_176252.1:n.107G>T
NR_176253.1:n.107G>T

Protein change:

A29S

Links:

dbSNP: rs142449183

NCBI 1000 Genomes Browser:

rs142449183

Molecular consequence:

NM_001199973.2:c.301-4117C>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001199974.2:c.178-4117C>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000169.3:c.85G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406747.1:c.85G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406748.1:c.85G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406749.1:c.85G>T - missense variant - [Sequence Ontology: SO:0001583]
NR_164783.1:n.107G>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176252.1:n.107G>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176253.1:n.107G>T - 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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MIMAG Metagenome-assembled Genome sample from Empedobacter falsenii
MIMAG Metagenome-assembled Genome sample from Empedobacter falsenii

biosample
membrane, 0min, replicate2
membrane, 0min, replicate2

biosample
wu:fb95b07 wu:fb95b07 [Danio rerio]
wu:fb95b07 wu:fb95b07 [Danio rerio]
Gene ID:323318

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001354915	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 15, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001414150	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 3, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002054362	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]
SCV002081353	Natera, Inc.	no assertion criteria provided	Uncertain significance (Aug 12, 2020)	germline	clinical testing

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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

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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001354915.3

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

Description

This missense variant replaces alanine with serine at codon 29 of the GLA protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with GLA-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is 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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001414150.4

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

Description

This sequence change replaces alanine with serine at codon 29 of the GLA protein (p.Ala29Ser). The alanine residue is moderately conserved and there is a moderate physicochemical difference between alanine and serine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with Fabry disease (Invitae). ClinVar contains an entry for this variant (Variation ID: 925806). 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 tolerated. 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, SCV002054362.1

#	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., SCV002081353.1

#	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: Sep 29, 2024

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