ClinVar Genomic variation as it relates to human health

p.Asp315Asp in exon 6 of GLA: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 0.02% (15/90617) of European chromosomes, including 5 hemizygotes, by the Genome Aggregation Databas e (gnomAD; http://gnomad.broadinstitute.org/; dbSNP rs151208856).

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.

The c.945C>T variant in GLA has not been previously reported in individuals with Fabry disease, but has been identified in 0.017% (16/92661) of European (non-Finnish) chromosomes, including 6 hemizygotes, and 0.014% (4/28052) of Latino chromosomes, including 1 hemizygote, by the Genome Aggregation Database (gnomAD; http://gnomad.broadinstitute.org/; dbSNP rs151208856). This variant has been seen in the general population at a greater frequency than expected for Fabry disease and is consistent with a benign role. This variant has been reported in ClinVar as likely benign by the Laboratoy for Molecular Medicine, Invitae, and the University Medical Center Groningen, as benign by GeneDx, and as a VUS by Praxis fuer Humangenetik Tuebingen (Variation ID: 42465). 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. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely benign. ACMG/AMP Criteria applied: BS1_supporting, BP4, BP7 (Richards 2015).

Variant summary: The GLA c.945C>T (p.Asp315Asp) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing (1 tool predicts a decreased affinity for a cryptic donor splice site). ESE finder predicts that this variant may affect a binding site for SF2/ASF. However, these predictions have yet to be confirmed by functional studies. This variant was found in 19/200260 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.000166 (15/90617) with 5 hemizygous occurrences, that exceeds the disease prevalence (1/50000), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases; nor evaluated for functional impact by in vivo/vitro studies. In addition, multiple clinical diagnostic laboratories classified this variant as likely benign/benign. Taken together, based mainly on the in silico predictions and the observed hemizygous occurrences this variant is classified as likely benign.

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).