ClinVar Genomic variation as it relates to human health

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.

This sequence variant is a single nucleotide duplication (dupC) at coding position 972 of the HPS1 gene that results in an early termition sigl 128 codons downstream of the frameshift at Met325. As it occurs in exon 11 of 20, this variant is predicted to generate a non-functiol allele through either the expression of a truncated protein or a loss of HPS1 expression due to nonsense-mediated decay. This is a previously reported variant (ClinVar 5278) that has been observed in homozygous or compound heterozygous state in many individuals and families affected by Hermansky-Pudlak syndrome (PMID: 8896559, 12442288, 14510955, 15952982, 16185271, 31141302, 31619213). This variant is present in 46 of 175586 alleles (0.0262%) in the gnomAD population dataset. Haploinsufficiency in HPS1 is a known mechanism of disease. Based upon the evidence, we consider this variant to be pathogenic. ACMG Criteria: BP2, PM3, PS4, PVS1

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).

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 8896559, 8274781, 19729668, 30791930, 31229681, 30387913, 31141302, 9497254, 14510955, 16185271, 32581362, 31589614, 32725903)

Variant summary: HPS1 c.972dupC (p.Met325HisfsX128) 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 frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.972dupC has been reported in the literature in the homozygous state in individuals affected with albinism and Hermansky-Pudlak Syndrome (e.g. Wei_2022). These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 34838614). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

This sequence change creates a premature translational stop signal (p.Met325Hisfs*128) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with Hermansky–Pudlak syndrome (PMID: 8896559, 14510955, 15952982, 16185271). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as insC974 and Pro324 frameshift. ClinVar contains an entry for this variant (Variation ID: 5278). For these reasons, this variant has been classified as Pathogenic.

The HPS1 c.972dupC variant is predicted to result in a frameshift and premature protein termination (p.Met325Hisfs*128). This variant has been reported in the homozygous and compound heterozygous states in individuals with Hermansky-Pudlak syndrome (referred to as Pro 324 frameshift, Oh et al. 1996. PubMed ID: 8896559; Okamura et al. 2019. PubMed ID: 31141302; Table S1, Wei et al. 2022. PubMed ID: 34838614). This variant is reported in 0.036% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in HPS1 are expected to be pathogenic. This variant is interpreted as pathogenic.