ClinVar Genomic variation as it relates to human health

Variant summary: HPS1 c.517C>T (p.Arg173X) 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. The variant allele was found at a frequency of 4e-06 in 247936 control chromosomes. c.517C>T has been reported in the literature in at-least two individuals affected with Hermansky-Pudlak Syndrome (example, Wei_2016, Theunissen_2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

The p.Arg173Ter variant in HPS1 has been reported in at least 2 individuals with Hermansky-Pudlak syndrome (PMID: 27593200, 28081892), and has been identified in 0.006% (1/16046) of African/African-American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs538274657). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. Of the 2 affected individuals, 1 was a compound heterozygote that carried a reported pathogenic variants in trans, which increases the likelihood that the p.Arg173Ter variant is pathogenic (VariationID: 21091 PMID: 28081892). This variant has also been reported in ClinVar (Variation ID#: 937794) and has been interpreted as Pathogenic by Women's Health and Genetics (Laboratory Corporation of America, LabCorp) and Invitae. This nonsense variant leads to a premature termination codon at position 173, which is predicted to lead to a truncated or absent protein. Loss of function of the HPS1 gene is an established disease mechanism in autosomal recessive Hermansky-Pudlak syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Hermansky-Pudlak syndrome. ACMG/AMP Criteria applied: PM3, PM2_supporting, PVS1 (Richards 2015).

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). The variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000937794 / PMID: 27593200). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

This sequence change creates a premature translational stop signal (p.Arg173*) in the HPS1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HPS1 are known to be pathogenic (PMID: 12442288, 16185271). This variant is present in population databases (rs538274657, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with clinical features of Hermansky-Pudlak Syndrome (PMID: 27593200, 28081892). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 937794). For these reasons, this variant has been classified as Pathogenic.