NM_000169.3(GLA):c.337T>C (p.Phe113Leu) AND Fabry disease

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Dec 11, 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:: RCV000991314.12

Allele description [Variation Report for NM_000169.3(GLA):c.337T>C (p.Phe113Leu)]

NM_000169.3(GLA):c.337T>C (p.Phe113Leu)

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.337T>C (p.Phe113Leu)

HGVS:

NC_000023.11:g.101403843A>G
NG_007119.1:g.9121T>C
NG_016327.1:g.641A>G
NM_000169.3:c.337T>CMANE SELECT
NM_001199973.2:c.301-8093A>G
NM_001199974.2:c.178-8093A>G
NP_000160.1:p.Phe113Leu
NP_000160.1:p.Phe113Leu
LRG_672t1:c.337T>C
LRG_672:g.9121T>C
LRG_672p1:p.Phe113Leu
NC_000023.10:g.100658831A>G
NM_000169.2:c.337T>C
NR_164783.1:n.359T>C
p.F113L
p.Phe113Ile

Protein change:

F113L; PHE113LEU

Links:

OMIM: 300644.0063; dbSNP: rs869312142

NCBI 1000 Genomes Browser:

rs869312142

Molecular consequence:

NM_001199973.2:c.301-8093A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001199974.2:c.178-8093A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000169.3:c.337T>C - missense variant - [Sequence Ontology: SO:0001583]
NR_164783.1:n.359T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Functional consequence:

effect on protein activity [Variation Ontology: 0053]

Observations:

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
SCV001134929	Center for Inherited Cardiovascular Diseases, IRCCS Fondazione Policlinico San Matteo	criteria provided, single submitter (Favalli et al. (J Am Coll Cardiol. 2016))	Pathogenic (Dec 16, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001426781	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jul 8, 2020)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 17555407, 19287194, 28728877, 31200018 Citation Link,
SCV002054442	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 15, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002081349	Natera, Inc.	no assertion criteria provided	Pathogenic (May 21, 2021)	germline	clinical testing
SCV002179147	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 11, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 16773563, 17555407, 32099817, 28492532

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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
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
Caucasian	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Genetic Screening of Anderson-Fabry Disease in Probands Referred From Multispecialty Clinics.

Favalli V, Disabella E, Molinaro M, Tagliani M, Scarabotto A, Serio A, Grasso M, Narula N, Giorgianni C, Caspani C, Concardi M, Agozzino M, Giordano C, Smirnova A, Kodama T, Giuliani L, Antoniazzi E, Borroni RG, Vassallo C, Mangione F, Scelsi L, Ghio S, et al.

J Am Coll Cardiol. 2016 Sep 6;68(10):1037-50. doi: 10.1016/j.jacc.2016.05.090.

PubMed [citation]

PMID:: 27585509

Effects of a chemical chaperone on genetic mutations in alpha-galactosidase A in Korean patients with Fabry disease.

Park JY, Kim GH, Kim SS, Ko JM, Lee JJ, Yoo HW.

Exp Mol Med. 2009 Jan 31;41(1):1-7.

PubMed [citation]

PMID:: 19287194
PMCID:: PMC2679280

See all PubMed Citations (9)

Details of each submission

From Center for Inherited Cardiovascular Diseases, IRCCS Fondazione Policlinico San Matteo, SCV001134929.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Caucasian	1	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	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001426781.1

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

Description

Variant summary: GLA c.337T>C (p.Phe113Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183395 control chromosomes. c.337T>C has been reported in the literature in numerous individuals affected with Fabry Disease and is reported as a variant causing late-onset disease (Oliveria_2020, Park_2009, Nowak_2017). The variant showed significantly reduced alpha-Gal activity in both patient fibroblasts and COS-7 cells transfected with the variant, and showed responsive to 1-deoxygalactonojirimycin (DGJ) (Park_2009, Ishii_2007). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#	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, SCV002054442.1

#	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., SCV002081349.1

#	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

From Invitae, SCV002179147.3

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

Description

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 113 of the GLA protein (p.Phe113Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Fabry disease, often with late onset (PMID: 16773563, 17555407, 32099817). It is commonly reported in individuals of Portuguese ancestry (PMID: 32099817). ClinVar contains an entry for this variant (Variation ID: 222218). 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 expected to disrupt GLA protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GLA function (PMID: 16773563, 17555407, 32099817). For these reasons, this variant has been classified as Pathogenic.

#	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: May 12, 2024

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