ClinVar Genomic variation as it relates to human health

The c.1423delC variant in the HPS5 gene has been reported previously in association with Hermansky-Pudlak syndrome, in an affected individual who was homozygous for the c.1423delC variant (reported as c.1081delC) and in an affected individual who was heterozygous for the c.1423delC variant, however no second HPS5 variant was identified (Ringeisen et al., 2013; Carmona-Rivera et al., 2011). The c.1423delC variant causes a frameshift starting with codon Leucine 475, changes this amino acid to a Serine residue, and creates a premature Stop codon at position 37 of the new reading frame, denoted p.Leu475SerfsX37. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.1423delC variant is observed in 18/246198 (0.007%) alleles in large population cohorts and no individuals were reported to be homozygous (Lek et al., 2016). We interpret c.1423delC as a likely pathogenic variant.

The HPS5 c.1423delC (p.Leu475SerfsTer37) variant results in a frameshift, and is predicted to result in premature termination of the protein. The p.Leu475SerfsTer37 variant has been reported in two studies in which it is found in two individuals with Hermansky-Pudlak syndrome including in one in a homozygous state and in one in a heterozygous state where a second variant was not detected (Carmona-Rivera et al. 2011; Ringeisen et al. 2013). Control data are unavailable for this variant, which is reported at a frequency of 0.00152 in the Ashkenazi Jewish population of the Genome Aggregation Database. Characterization of the heterozygous patient's fibroblasts revealed a complete absence of HPS5 protein (Carmona-Rivera et al. 2011). Based on the evidence and the potential impact of frameshift variants, the p.Leu475SerfsTer37 variant is classified as a variant of unknown significance, but suspicious for pathogenicity for Hermansky-Pudlak syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Variant summary: HPS5 c.1423delC (p.Leu475SerfsX37) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been associated with Hermansky-Pudlak Syndrome in HGMD and classified as pathogenic in ClinVar. The variant allele was found at a frequency of 8e-05 in 251438 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in HPS5 causing Hermansky-Pudlak Syndrome (8e-05 vs 0.00047), allowing no conclusion about variant significance. c.1423delC has been reported in the literature in individuals affected with Hermansky-Pudlak Syndrome (Carmona-Rivera_2011, Ringeisen_2013). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified as VUS (n=1), Likely Pathogenic, (n=2) and Pathogenic(n=3). Based on the evidence outlined above, the variant was classified as likely pathogenic.

This sequence change creates a premature translational stop signal (p.Leu475Serfs*37) in the HPS5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HPS5 are known to be pathogenic (PMID: 12548288, 15296495, 21833017, 26785811). This variant is present in population databases (rs766602179, gnomAD 0.2%). This premature translational stop signal has been observed in individual(s) with Hermansky-Pudlak syndrome (PMID: 21833017, 23607980). This variant is also known as 1081delC. ClinVar contains an entry for this variant (Variation ID: 431164). For these reasons, this variant has been classified as Pathogenic.