NM_000169.3(GLA):c.454T>G (p.Tyr152Asp) AND Fabry disease

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Sep 2, 2021
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:: RCV001341700.8

Allele description [Variation Report for NM_000169.3(GLA):c.454T>G (p.Tyr152Asp)]

NM_000169.3(GLA):c.454T>G (p.Tyr152Asp)

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.454T>G (p.Tyr152Asp)

HGVS:

NC_000023.11:g.101401725A>C
NG_007119.1:g.11239T>G
NM_000169.3:c.454T>GMANE SELECT
NM_001199973.2:c.300+6268A>C
NM_001199974.2:c.177+9903A>C
NM_001406747.1:c.577T>G
NM_001406748.1:c.454T>G
NM_001406749.1:c.577T>G
NP_000160.1:p.Tyr152Asp
NP_000160.1:p.Tyr152Asp
NP_001393676.1:p.Tyr193Asp
NP_001393677.1:p.Tyr152Asp
NP_001393678.1:p.Tyr193Asp
LRG_672t1:c.454T>G
LRG_672:g.11239T>G
LRG_672p1:p.Tyr152Asp
NC_000023.10:g.100656713A>C
NM_000169.2:c.454T>G
NR_164783.1:n.476T>G
NR_176252.1:n.476T>G
NR_176253.1:n.476T>G

Protein change:

Y152D

Links:

dbSNP: rs1928323615

NCBI 1000 Genomes Browser:

rs1928323615

Molecular consequence:

NM_001199973.2:c.300+6268A>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001199974.2:c.177+9903A>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000169.3:c.454T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406747.1:c.577T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406748.1:c.454T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406749.1:c.577T>G - missense variant - [Sequence Ontology: SO:0001583]
NR_164783.1:n.476T>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176252.1:n.476T>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_176253.1:n.476T>G - 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
SCV001535583	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Sep 2, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 25531941, 30474596, 30477121, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001535583

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Sep 2, 2021)

germline

clinical testing

PubMed (4)
[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

Foot process effacement is an early marker of nephropathy in young classic Fabry patients without albuminuria.

Tøndel C, Kanai T, Larsen KK, Ito S, Politei JM, Warnock DG, Svarstad E.

Nephron. 2015;129(1):16-21. doi: 10.1159/000369309. Epub 2014 Dec 17.

PubMed [citation]

PMID:: 25531941

Identification of new α-galactosidase A mutation responsible for Fabry disease: A case report.

Battaglia Y, Scalia S, Rinaldi R, Storari A, Mignani R, Russo D, Duro G.

Clin Nephrol. 2019 Feb;91(2):126-128. doi: 10.5414/CN109501. No abstract available.

PubMed [citation]

PMID:: 30474596

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001535583.4

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

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Tyr152 amino acid residue in GLA. Other variant(s) that disrupt this residue have been observed in individuals with GLA-related conditions (PMID: 25531941, 30474596, 30477121), which suggests that this may be a clinically significant amino acid residue. 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. ClinVar contains an entry for this variant (Variation ID: 1038401). This variant has been observed in individual(s) with clinical features of Fabry disease (Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces tyrosine with aspartic acid at codon 152 of the GLA protein (p.Tyr152Asp). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and aspartic acid.

#	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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