ClinVar Miner

Submissions for variant NM_007216.4(HPS5):c.1081del (p.Leu361fs) (rs766602179)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000599122 SCV000709991 likely pathogenic not provided 2018-02-21 criteria provided, single submitter clinical testing 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.
NIHR Bioresource Rare Diseases, University of Cambridge RCV000852025 SCV000899501 likely pathogenic Hermansky-Pudlak syndrome 2019-02-01 criteria provided, single submitter research
Illumina Clinical Services Laboratory,Illumina RCV000496925 SCV000915517 uncertain significance Hermansky-Pudlak syndrome 5 2018-01-12 criteria provided, single submitter clinical testing 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.
OMIM RCV000496925 SCV000586805 pathogenic Hermansky-Pudlak syndrome 5 2017-08-02 no assertion criteria provided literature only

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