ClinVar Miner

Submissions for variant NM_000195.5(HPS1):c.972dup (p.Met325fs) (rs281865082)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000520943 SCV000616745 pathogenic not provided 2018-07-02 criteria provided, single submitter clinical testing The c.972dupC variant in the HPS1 gene has been reported previously, using alternate nomenclature of T322insC or Pro 324 frameshift, in association with autosomal recessive Hermansky-Pudlak syndrome when present in the homozygous state or when present with another disease-causing HPS1 variant, although parental studies were not performed to determine the phase of these two variants (Oh et al., 1996; Oh et al., 1998). The c.972dupC variant causes a frameshift starting with codon Methionine 325, changes this amino acid to a Histidine residue, and creates a premature Stop codon at position 128 of the new reading frame, denoted p.M325HfsX128. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.972dupC variant is observed in 2/8696 alleles (0.023%) from individuals of African background, and 4/30,798 global alleles (0.013%) with no homozygous control individuals reported, in large population cohorts (Lek et al., 2016). We interpret c.972dupC as a pathogenic variant.
GeneReviews RCV000005596 SCV000040539 pathologic Hermansky-Pudlak syndrome 1 2012-10-11 no assertion criteria provided curation Converted during submission to Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000612428 SCV000713081 pathogenic Hermansky-Pudlak syndrome 2017-02-27 criteria provided, single submitter clinical testing The p.Met325fs variant in HPS1 has been reported in 5 Caucasian and 3 Japanese i ndividuals with Hermansky-Pudlak syndrome (Oh 1996, Oh 1998, Gonzalez-Conejero 2 003, Ito 2005). Three individuals were homozygous for this variant and 5 were co mpound heterozygous with a second truncating variant in HPS1. The homozygous all ele also segregated with disease in 5 additional family members in a consanguine ous Swiss family (Oh 1996). This variant has been reported in ClinVar (Variation ID 5278). This variant has been identified in 0.4% (31/8034) of European chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs281865083). This frequency is low enough to be consistent with a recess ive carrier frequency. In vitro functional studies provide some evidence that th e p.Met325fs variant may impact protein function (Gonzalez-Conejero 2003). This variant is predicted to cause a frameshift, which alters the protein?s amino aci d sequence beginning at position 325 and leads to a premature termination codon 128 amino acids downstream. This alteration is then predicted to lead to a trunc ated or absent protein. In summary, this variant meets criteria to be classified as pathogenic for HPS in an autosomal recessive manner based upon prevalence in cases and segregation studies.
NIHR Bioresource Rare Diseases, University of Cambridge RCV000612428 SCV000899377 likely pathogenic Hermansky-Pudlak syndrome 2019-02-01 criteria provided, single submitter research
OMIM RCV000005596 SCV000025778 pathogenic Hermansky-Pudlak syndrome 1 1998-03-01 no assertion criteria provided literature only

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