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

dbSNP: rs869312142

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Inherited Cardiovascular Diseases, IRCCS Fondazione Policlinico San Matteo	RCV000991314	SCV001134929	pathogenic	Fabry disease	2019-12-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000991314	SCV001426781	pathogenic	Fabry disease	2020-07-08	criteria provided, single submitter	clinical testing	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.
Revvity Omics, Revvity	RCV001781617	SCV002024304	pathogenic	not provided	2022-06-10	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000991314	SCV002054442	pathogenic	Fabry disease	2021-07-15	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000991314	SCV002179147	pathogenic	Fabry disease	2023-12-11	criteria provided, single submitter	clinical testing	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.
Ambry Genetics	RCV002453751	SCV002614534	pathogenic	Cardiovascular phenotype	2020-01-16	criteria provided, single submitter	clinical testing	The p.F113L pathogenic mutation (also known as c.337T>C), located in coding exon 2 of the GLA gene, results from a T to C substitution at nucleotide position 337. The phenylalanine at codon 113 is replaced by leucine, an amino acid with highly similar properties. This mutation was detected in an adult male with residual alpha-galactosidase A enzyme activity and reported cardiac-variant Fabry disease whose carrier mother also had cardiac manifestations (Eng CM et al. Mol. Med., 1997 Mar;3:174-82). Subsequently, this mutation has been reported as a Portuguese founder mutation, having been detected in multiple individuals and families with Fabry disease, frequently presenting with late-onset cardiac-variant phenotoype; however, additional features of Fabry disease in individuals with this mutation have also been reported (Spada M et al. Am. J. Hum. Genet., 2006 Jul;79:31-40; Park JY et al. Exp. Mol. Med., 2009 Jan;41:1-7; Nowak A et al. Mol. Genet. Metab., 2018 02;123:148-153; Azevedo O et al. Mol. Genet. Metab., 2019 Jul; Oliveira JP et al. Eur J Med Genet, 2019 Jun;103703). In addition, several functional assays have shown this mutation to result in reduced enzyme activity in vitro (Spada M et al. Am. J. Hum. Genet., 2006 Jul;79:31-40; Wu X et al. Hum. Mutat., 2011 Aug;32:965-77; Ishii S et al. Biochem. J., 2007 Sep;406:285-95; Park JY et al. Exp. Mol. Med., 2009 Jan;41:1-7). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV001781617	SCV005201469	pathogenic	not provided	2024-03-08	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25382311, 33036343, 25468652, 31519519, 33119553, 31200018, 33994139, 16773563, 19287194, 24386359, 21598360, 9100224, 17555407, 28728877, 32099817)
OMIM	RCV001636724	SCV001852727	pathogenic	Fabry disease, cardiac variant	2021-09-09	no assertion criteria provided	literature only
Natera, Inc.	RCV000991314	SCV002081349	pathogenic	Fabry disease	2021-05-21	no assertion criteria provided	clinical testing