Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Color Diagnostics, |
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. |
| Invitae | RCV001187084 | SCV004299637 | uncertain significance | Fabry disease | 2023-02-16 | criteria provided, single submitter | clinical testing | 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). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Fabry disease (PMID: 28496025). ClinVar contains an entry for this variant (Variation ID: 925251). 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 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. 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. |