ClinVar

Description

p.Ala1067Val (c.3200C>T) in exon 23 the DSP gene (NM_004415.2; 6:7579623C>T; GRCh37) Given the absent case data on this variant and that rare, missense variation is common in the general population, we consider this variant a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Missense variation in DSP must be interpreted with caution. This variant is novel. This variant has not been reported in individuals with cardiomyopathy. Another variant at this position (p.Ala1067Ser) has been reported in ClinVar in one individual with familial hypertrophy cardiomyopathy and is classified as a variant of uncertain significance. Multiple studies have found that rare, missense variation in DSP is common in the general population: According to the ExAC database's constraint data, DSP appears to be fairly tolerant to missense variation (Z=0.91), but not to loss of function/truncating variation (pLI - 1.000). This is supported by literature. In a study examining the genetic underpinnings of ARVC, 16% of 427 controls were found to have missense variants (Kapplinger et al., 2011). Kapplinger and colleagues also proposed that there is a "hot spot" of missense variation in DSP that causes ARVC - from amino acids 250-604. In another study that compared the genetic variation between pooled patients with cardiomyopathy and individuals in the general population via the ExAC database (60,000 control individuals), missense variation in DSP was NOT significantly enriched in cases of DCM or ARVC (Walsh et al., 2016). Another study (Amr et al., 2016) examined the prevalence of genetic variation in cardiomyopathy cases versus controls and determined that missense variation in DSP in general confers a minimal increase in disease risk (OR=0.62). This is in contrast to the high increase in disease risk loss-of-function variation in DSP confers (OR=18.21). Per the test report, "computational prediction tools and conservation analysis suggest that the p.Ala1067Val variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity." The alanine at codon 1067 is not completely conserved across species: elephants, chickens, and other lower vertebrates have other amino acids present at this location. Neighboring amino acids are not completely conserved across species. A nearby variant is reported as pathogenic; however, this is a truncating variant (p.Tyr1065Ter). Loss-of-function variants are a known mechanism of disease in DSP. Furthermore, according to the test report, this variant may introduce a novel splice site: "while this variant is located within an exon, computational tools suggest the creation of a novel splice site; however, this information is not predictive enough to determine pathogenicity." This variant is not present in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. The average coverage at that site in gnomAD is 87x in exomes and 34x in genomes. Another variant at this codon, p.Ala1067Ser is present in 1 out of 11,149 individuals of European descent.