Submissions for variant NM_000195.5(HPS1):c.1189del (p.Gln397fs)

dbSNP: rs281865084

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000020181	SCV000359659	likely pathogenic	Hermansky-Pudlak syndrome 1	2017-04-27	criteria provided, single submitter	clinical testing	The HPS1 c.1189delC (p.Gln397SerfsTer2) variant results in a frameshift and is predicted to cause a premature termination of the protein. The variant is reported in six studies in which it is found in a total of nine out of 43 individuals with Hermansky-Pudlak syndrome (HPS), including two homozygotes, one hemizygote, and six compound heterozygotes, and in four unaffected heterozygous family members (Oh et al. 1998; Shotelersuk et al. 1998; Griffin et al. 2005; Huizing et al. 2007; Sandrock et al. 2010; Westmoreland et al. 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.00012 in the European (non-Finnish) population of the Exome Aggregation Consortium. Northern blot analysis of fibroblasts from the hemizygous individual showed significantly reduced HPS RNA (Shotelersuk et al. 1998). Based on the collective evidence, the p.Gln397SerfsTer2 variant is classified as pathogenic for Hermansky-Pudlak syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000851664	SCV000899448	pathogenic	Hermansky-Pudlak syndrome	2019-02-01	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000796076	SCV000935571	pathogenic	not provided	2025-01-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln397Serfs*2) 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 (rs281865084, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with HPS1-related conditions (PMID: 9497254, 20514622, 28081892). This variant is also known as E397delC. ClinVar contains an entry for this variant (Variation ID: 21091). For these reasons, this variant has been classified as Pathogenic.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000020181	SCV001367002	pathogenic	Hermansky-Pudlak syndrome 1	2019-09-16	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2,PM3,PP4. This variant was detected in homozygous state.
Revvity Omics, Revvity	RCV000020181	SCV002025014	pathogenic	Hermansky-Pudlak syndrome 1	2021-07-01	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000851664	SCV002097057	pathogenic	Hermansky-Pudlak syndrome	2021-11-29	criteria provided, single submitter	curation	The p.Gln397fs variant in HPS1 has been reported in at least 9 individuals with Hermansky-Pudlak syndrome (PMID: 31619213, 26806224, 28081892, 20514622, 9497254, 15952982), segregated with disease in 2 affected relatives from 2 families (PMID: 20514622) and has been identified in 0.01% (19/128472) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs281865084). 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. This variant has also been reported in ClinVar (Variation ID#: 21091) and has been interpreted as Likely Pathogenic or Pathogenic by Illumina Clinical Services Laboratory (Illumina), Centre for Mendelian Genomics (University Medical Centre Ljubljana), NIHR Bioresource Rare Diseases (University of Cambridge), Invitae, and GeneReviews. Of the at least 9 affected individuals, 2 of those were homozygotes, and 1 were compound heterozygote that carried a reported likely pathogenic variants in trans, which increases the likelihood that the p.Gln397fs variant is pathogenic (PMID: 17365864, 9497254, 20514622). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 397 and leads to a premature termination codon 2 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, PVS1, PP1_moderate (Richards 2015).
Fulgent Genetics, Fulgent Genetics	RCV000020181	SCV002810326	pathogenic	Hermansky-Pudlak syndrome 1	2024-04-17	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000020181	SCV004199919	pathogenic	Hermansky-Pudlak syndrome 1	2024-03-26	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000020181	SCV004697332	pathogenic	Hermansky-Pudlak syndrome 1	2024-02-20	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000020181	SCV005091097	pathogenic	Hermansky-Pudlak syndrome 1	2024-02-15	criteria provided, single submitter	clinical testing	PVS1, PM2, PP5 - The variant has been reported in ClinVar as Pathogenic by other laboratories (Variation ID 21091). This variant has been previously reported as causative (PMID:31619213).
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	RCV000020181	SCV005397379	pathogenic	Hermansky-Pudlak syndrome 1	2023-08-16	criteria provided, single submitter	clinical testing	This sequence variant is a single nucleotide deletion (delC) at coding position 1189 of the HPS1 gene that results in an early termition sigl 2 codons downstream of the frameshift at Gln397. As it occurs in exon 13 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 21091) that has been observed in homozygous or compound heterozygous state in many individuals and families affected by Hermansky-Pudlak syndrome (PMID: 9497254, 9705234, 12442288, 15952982, 20514622, 26806224). This variant is present in 19 of 281342 alleles (0.0068%) 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: PM3, PS4, PVS1
GeneReviews	RCV000020181	SCV000040514	not provided	Hermansky-Pudlak syndrome 1		no assertion provided	literature only
Clinical Genetics, Academic Medical Center	RCV000796076	SCV001924301	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000796076	SCV001973170	pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000851664	SCV002076663	pathogenic	Hermansky-Pudlak syndrome	2020-07-24	no assertion criteria provided	clinical testing
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV000020181	SCV002515570	pathogenic	Hermansky-Pudlak syndrome 1		no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004754268	SCV005361831	pathogenic	HPS1-related disorder	2024-07-30	no assertion criteria provided	clinical testing	The HPS1 c.1189delC variant is predicted to result in a frameshift and premature protein termination (p.Gln397Serfs*2). This variant has been reported in individuals with Hermansky-Pudlak syndrome in the compound heterozygous states (Marti et al. 2017. PubMed ID: 28976636; supplemental Table 3, Downes et al. 2019. PubMed ID: 31064749) This variant is reported in 0.015% 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.