Submissions for variant NM_000195.5(HPS1):c.355del (p.His119fs)

gnomAD frequency: 0.00002  dbSNP: rs281865075

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001067590	SCV001232658	pathogenic	not provided	2024-10-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.His119Thrfs*5) 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 (rs281865075, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with Hermansky-Pudlak syndrome (PMID: 12442288). This variant is also known as c.561delC. ClinVar contains an entry for this variant (Variation ID: 21103). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000020193	SCV001752682	pathogenic	Hermansky-Pudlak syndrome 1	2024-06-25	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001275007	SCV002097066	pathogenic	Hermansky-Pudlak syndrome	2021-11-29	criteria provided, single submitter	curation	The p.His119fs variant in HPS1 has been reported in 3 individuals with Hermansky-Pudlak syndrome (PMID: 12442288, 20514622, DOI: 10.26502/acmcr.96550313) and has been identified in 0.002% (3/129066) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs281865075). 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. This variant has also been reported in ClinVar (Variation ID#: 21103) and has been interpreted as pathogenic by Invitae, Natera, Inc., and GeneReviews. Of the 3 affected individuals, all were compound heterozygotes that carried a reported pathogenic variant in trans or with unknown phase, which increases the likelihood that the p.His119fs variant is pathogenic (VariationID: 21091; PMID: 12442288, 20514622, DOI: 10.26502/acmcr.96550313). In vitro functional studies provide some evidence that the p.His119fs variant may slightly impact protein function (PMID: 12442288). 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 119 and leads to a premature termination codon 5 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_strong, PM2_supporting, PVS1, PS3_supporting (Richards 2015).
GeneDx	RCV001067590	SCV003918401	pathogenic	not provided	2022-10-17	criteria provided, single submitter	clinical testing	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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31589614, 31898847, 20514622, 12442288, Boeckelmann2020[paper])
Baylor Genetics	RCV000020193	SCV004199914	pathogenic	Hermansky-Pudlak syndrome 1	2023-10-26	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001275007	SCV001459683	pathogenic	Hermansky-Pudlak syndrome	2020-09-16	no assertion criteria provided	clinical testing