NM_000169.3(GLA):c.358C>G (p.Leu120Val) AND Fabry disease

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Oct 10, 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:: RCV003066353.3

Allele description [Variation Report for NM_000169.3(GLA):c.358C>G (p.Leu120Val)]

NM_000169.3(GLA):c.358C>G (p.Leu120Val)

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.358C>G (p.Leu120Val)

HGVS:

NC_000023.11:g.101403822G>C
NG_007119.1:g.9142C>G
NG_016327.1:g.620G>C
NM_000169.3:c.358C>GMANE SELECT
NM_001199973.2:c.301-8114G>C
NM_001199974.2:c.178-8114G>C
NM_001406747.1:c.481C>G
NM_001406748.1:c.358C>G
NM_001406749.1:c.481C>G
NP_000160.1:p.Leu120Val
NP_000160.1:p.Leu120Val
NP_001393676.1:p.Leu161Val
NP_001393677.1:p.Leu120Val
NP_001393678.1:p.Leu161Val
LRG_672t1:c.358C>G
LRG_672:g.9142C>G
LRG_672p1:p.Leu120Val
NC_000023.10:g.100658810G>C
NM_000169.2:c.358C>G
NR_164783.1:n.380C>G
NR_176252.1:n.380C>G
NR_176253.1:n.380C>G

Protein change:

L120V

Molecular consequence:

NM_001199973.2:c.301-8114G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001199974.2:c.178-8114G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000169.3:c.358C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406747.1:c.481C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406748.1:c.358C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406749.1:c.481C>G - missense variant - [Sequence Ontology: SO:0001583]
NR_164783.1:n.380C>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
SCV003445173	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Oct 10, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 23935525, 19621417, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003445173

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Oct 10, 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

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

Newborn screening for Fabry disease in Taiwan reveals a high incidence of the later-onset GLA mutation c.936+919G>A (IVS4+919G>A).

Hwu WL, Chien YH, Lee NC, Chiang SC, Dobrovolny R, Huang AC, Yeh HY, Chao MC, Lin SJ, Kitagawa T, Desnick RJ, Hsu LW.

Hum Mutat. 2009 Oct;30(10):1397-405. doi: 10.1002/humu.21074.

PubMed [citation]

PMID:: 19621417
PMCID:: PMC2769558

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV003445173.2

#	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 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects GLA function (PMID: 19621417, 23935525). 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. This missense change has been observed in individual(s) with clinical features of Fabry disease (PMID: 19621417; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 120 of the GLA protein (p.Leu120Val).

#	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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