ClinVar Genomic variation as it relates to human health

Variant classified as Uncertain Significance - Favor Benign. The 639+6A>C varian t (GLA) has not been previously reported but has been identified by our laborato ry in 1 individual with HCM who carried another possibly disease causing variant in the MYBPC3 gene. This variant occurs in the 5' splice site consensus sequenc e, but not in the invariant +1 or +2 positions. Computational tools do not predi ct an impact on splicing, though their accuracy is unknown. This variant is less likely disease causing but additional information is needed to confirm this.

This sequence change falls in intron 4 of the GLA gene. It does not directly change the encoded amino acid sequence of the GLA protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs200096940, gnomAD 0.006%). This variant has been observed in individual(s) with clinical features of hypertrophic cardiomyopathy (PMID: 22805550). ClinVar contains an entry for this variant (Variation ID: 42457). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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 is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

The c.639+6A>C variant in GLA has been reported in at least 1 individual with Fabry disease (PMID:22805550), and has been identified in 0.005% (1/15710) and 0.006% (4/78727) of European (Finnish) and European (non-Finnish) chromosomes, respectively, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs200096940). Although this variant has been seen in the general population, its frequency is low enough to be consistent with Fabry disease. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported in ClinVar as a VUS by the Laboratory for Molecular Medicine and as likely benign by GeneDx. (ID:42457). Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. One affected individuals with this variant had an alternative molecular basis for Fabry disease, suggesting that this variant may not be pathogenic. In summary, while the clinical significance of the c.639+6A>C variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: BS2, BP5, BP7, BP4, PM2_supporting (Richards 2015).