Submissions for variant NM_000169.3(GLA):c.717A>G (p.Ile239Met)

dbSNP: rs1928192530

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001187084	SCV001353748	likely pathogenic	Fabry disease	2019-12-04	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with methionine at codon 239 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. This variant has been reported in a female individual affected with Fabry disease and hypertrophic cardiomyopathy (PMID: 28496025). In this proband's 3-generation family, this variant was observed in 2 females and 1 male affected with hypertrophic cardiomyopathy and in 2 females affected with left ventricular hypertrophy. One female carrier at age 26 did not exhibit cardiac phenotype, but showed increased lyso-Gb3 levels as with all other carriers in this family. One affected male showed significantly reduced GLA enzyme levels. Six unaffected individuals from this family did not carry this variant. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant occurring at the same amino acid position, p.Ile239Thr, has been reported in a male affected with Fabry disease (PMID: 15100373), suggesting that isoleucine at this position is important for GLA protein function. Based on the available evidence, this variant is classified as Likely Pathogenic.
3billion	RCV001187084	SCV002572563	likely pathogenic	Fabry disease	2022-09-01	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.45; 3Cnet: 0.89). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with GLA-related disorder, and reported to segregate in more than 5 affected family members (ClinVar ID: VCV000925251/ PMID: 28496025). A different missense change at the same codon (p.Ile239Thr) has been reported to be associated with GLA-related disorder (PMID: 15100373). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001187084	SCV004299637	uncertain significance	Fabry disease	2023-02-16	criteria provided, single submitter	clinical testing	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. This variant disrupts the p.I239 amino acid residue in GLA. Other variant(s) that disrupt this residue have been observed in individuals with GLA-related conditions (PMID: 15100373, 28496025), which suggests that this may be a clinically significant amino acid residue. 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. ClinVar contains an entry for this variant (Variation ID: 925251). This missense change has been observed in individual(s) with Fabry disease (PMID: 28496025). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 239 of the GLA protein (p.Ile239Met).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001187084	SCV004848331	likely pathogenic	Fabry disease	2019-12-10	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory