ClinVar Genomic variation as it relates to human health

Although the c.1125_1140del16 mutation in the GLA gene has not been reported to our knowledge, this pathogenic variant causes a shift in reading frame starting at codon Valine 376, changing it to a Proline, and creating a premature stop codon at position 10 of the new reading frame, denoted p.Val376ProfsX10. This variant is expected to result in an abnormal, truncated protein product by replacing the last 54 amnio acids with 9 incorrect amino acids. Multiple other frameshift mutations downstream of this position in the GLA gene have been reported in HGMD in association with Fabry disease (Stenson P et al., 2014). Furthermore, the c.1125_1140del16 variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.In summary, c.1125_1140del16 in the GLA gene is interpreted as a disease-causing variant

This sequence change results in a premature translational stop signal in the GLA gene (p.Val376Profs*10). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 40 amino acids of the GLA protein. This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro409 amino acid residue in GLA. Other variants that disrupt this residue have been observed in individuals with GLA-related conditions (PMID: 12428061, 21598360, 11668641, 12428061, Invitae), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the affected amino acids is currently unknown. This variant has been observed in an individual affected with Fabry disease (Invitae).  ClinVar contains an entry for this variant (Variation ID: 234993).

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. GLA p.Val376ProfsX10 Given that this is a loss of function variant in a gene where loss of function variants are known to cause disease and the absence of this type of variant in the general population, we consider this variant likely pathogenic. The variant has not been reported with disease before. The variant is in the 7th and last exon. This mutation is expected to result in an abnormal, truncated protein product by replacing the last 54 amnio acids with 9 incorrect amino acids. There are 11 frameshift GLA vairants in ClinVar, all are listed as pathogenic but only one has multiple submitters. Of note, only one of these variants is more distal than this variant. However, multiple other frameshift mutations downstream of this position in the GLA gene have been reported in HGMD in association with Fabry disease (Stenson P et al., 2014). There are 23 nonsense GLA variants in ClinVar, all are listed as pathogenic, three have multiple submitters. The location of the V376PfsX10 variant, in the last exon of the gene, makes it unlikely to be subject to nonsense mediated decay; rather, it would produce a misfolded protein with a shortened polypeptide chain. Several truncation variants downstream of the V376PfsX10 variant have been reported in association with classic Fabry disease: Q386X, W399X (Mol Med. 1997 Mar; 3(3): 174–182.); E398X (Am J Hum Genet. 1993 Dec;53(6):1186-97.) In addition, exon 7 is the site of ~30% of small deletions and duplications < 65 nucleotides, according to data collected though the Fabry Outcome Survey Registry and review of the literature (Acta Paediatr Suppl. 2005 Mar;94(447):87-92; D. Elstein et al (eds) Fabry Disease, DOI 10.1007/978-90-481-9033-1_1). The variant isn't present in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of October 13, 2015). There are also no other loss of function variants.However, it is important to note that a deletion of this size could be missed with ExAC's methods. Nonetheless, no nonsense variants or smaller indels are present in this dataset.