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

dbSNP: rs281865082

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001058424	SCV001222992	pathogenic	not provided	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Met325Trpfs*6) 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 individuals with Hermansky–Pudlak syndrome (PMID: 19334085, 27593200). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5280). For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000005598	SCV001737339	pathogenic	Hermansky-Pudlak syndrome 1	2021-06-10	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001058424	SCV002067348	pathogenic	not provided	2019-07-09	criteria provided, single submitter	clinical testing	DNA sequence analysis of the HPS1 gene demonstrated a one base pair deletion in exon 11, c.972del. This sequence change results in an amino acid frameshift and creates a premature stop codon 5 amino acids downstream of the sequence change, p.Met325Trpfs*6. This sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated HPS1 protein with potentially abnormal function. This sequence change has been described in the gnomAD database with a population frequency of 0.012% in African subpopulation (dbSNP rs281865082). This sequence change has previously been described in patients with Hermansky-Pudlak syndrome in both homozygous and compound heterozygous states (PMID: 20662851, PMID: 19334085, PMID: 8896559). Functional studies have shown results that suggest a lack of function of the protein (PMID: 21833017). These collective evidences indicate that this sequence change is pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001273031	SCV002097070	pathogenic	Hermansky-Pudlak syndrome	2021-11-29	criteria provided, single submitter	curation	The p.Met325fs (c.972del) variant in HPS1 has been reported in at least 4 individuals with Hermansky-Pudlak syndrome (PMID: 27593200, 19334085, 9705234, 9497254), segregated with disease in 2 affected relatives from 2 families (PMID: 19334085, 9705234) and has been identified in 0.09% (15/17454) of European (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. Of the 4 affected individuals, 1 was compound heterozygote that carried a reported pathogenic variant in trans, which increases the likelihood that the p.Met325fs variant is pathogenic (VariationID: 21091; PMID: 9705234). This variant has also been reported in ClinVar (Variation ID#: 5280) and has been interpreted as pathogenic by Invitae, Nilou-Genome Lab, OMIM, Natera, Inc., and GeneReviews. In vitro functional studies provide some evidence that the p.Met325fs variant may impact protein function (PMID: 9705234). 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 6 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, PVS1 , PS3_moderate (Richards 2015).
Fulgent Genetics, Fulgent Genetics	RCV000005598	SCV002798701	pathogenic	Hermansky-Pudlak syndrome 1	2022-01-07	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000005598	SCV004199916	pathogenic	Hermansky-Pudlak syndrome 1	2023-10-25	criteria provided, single submitter	clinical testing
OMIM	RCV000005598	SCV000025780	pathogenic	Hermansky-Pudlak syndrome 1	1998-03-01	no assertion criteria provided	literature only
GeneReviews	RCV000005598	SCV000040538	not provided	Hermansky-Pudlak syndrome 1		no assertion provided	literature only
Natera, Inc.	RCV001273031	SCV001455567	pathogenic	Hermansky-Pudlak syndrome	2020-09-16	no assertion criteria provided	clinical testing