Description
The p.Met325fs (c.972dup) variant in HPS1 has been reported in at least 9 individuals with Hermansky-Pudlak syndrome (PMID: 9497254, 14510955, 16185271, 31141302, 8896559), segregated with disease in 5 affected relatives from 1 family (PMID: 8896559) and has been identified in 0.04% (26/71358) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs281865083). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. It is of note that this variant occurs in a homopolymer repeat, which could indicate that it exists as an artifact from sequencing. However, disease-causing variants have been reported in homopolymer regions, so this is not enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID#: 5278) and has been interpreted as likely pathogenic or pathogenic by NIHR Bioresource Rare Diseases (University of Cambridge), GeneDx, Laboratory for Molecular Medicine (Partners HealthCare Personalized Medicine), Institute of Human Genetics (University of Leipzig Medical Center), Center for Pediatric Genomic Medicine (Children's Mercy Hospital and Clinics), OMIM, Natera, Inc., NIHR Bioresource Rare Diseases (University of Cambridge), Invitae, and GeneReviews. Of the at least 9 affected individuals, 3 of those were homozygotes, which increases the likelihood that the p.Met325fs variant is pathogenic (PMID: 8896559, 9497254). In vitro functional studies provide some evidence that the p.Met325fs variant may slightly impact protein function (PMID: 14510955). However, these types of assays may not accurately represent biological function. This variant is predicted to cause a frameshift, which alters the protein’s amino acid 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 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, PP1_strong, PVS1, PS3_moderate (Richards 2015).
| # | Sample | Method | Observation |
|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
|---|
| 1 | germline | unknown | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |
