Submissions for variant NM_000195.5(HPS1):c.1472_1487dup (p.His497fs)

dbSNP: rs281865163

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000482079	SCV000344601	pathogenic	not provided	2016-09-21	criteria provided, single submitter	clinical testing
GeneDx	RCV000482079	SCV000565067	pathogenic	not provided	2020-04-02	criteria provided, single submitter	clinical testing	Frameshift variant that results in nonsense mediated mRNA decay (Hazelwood et al., 1997) in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 29445374, 8896559, 9345105, 30055995, 20662851, 9562579, 31898847)
Genetic Services Laboratory, University of Chicago	RCV000005595	SCV000595166	pathogenic	Hermansky-Pudlak syndrome 1	2015-10-14	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000614559	SCV000711718	pathogenic	Hermansky-Pudlak syndrome	2017-09-25	criteria provided, single submitter	clinical testing	The p.His497fs variant in HPS1 has been reported in 22 homozygous individuals wi th Hermansky-Pudlak Syndrome and has been described as founder variant in Puerto Rican population (Oh 1996). This variant has been identified in 8/34416 Latino chromosomes by the by the Genome Aggregation Database (gnomAD, http://gnomad.bro adinstitute.org; dbSNP rs281865163). This variant is predicted to cause a frames hift, which alters the protein?s amino acid sequence beginning at position 497 a nd leads to a premature termination codon 89 amino acids downstream. This altera tion is then predicted to lead to a truncated or absent protein. In summary, thi s variant meets criteria to be classified as pathogenic for Hermansky-Pudlak Syn drome in an autosomal recessive manner based on evidence in the literature and t he predicted impact of this variant on the protein. ACMG/AMP Criteria applied: P VS1, PM3_VS, PS4 (Richards 2015).
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000005595	SCV000844947	pathogenic	Hermansky-Pudlak syndrome 1	2018-10-19	criteria provided, single submitter	clinical testing
Invitae	RCV000482079	SCV000959691	pathogenic	not provided	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.His497Glnfs*90) 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 (rs281865163, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with Hermansky-Pudlak syndrome (PMID: 8896559, 9562579, 20662851). It is commonly reported in individuals of Puerto Rican ancestry (PMID: 8896559, 9562579, 20662851). ClinVar contains an entry for this variant (Variation ID: 5277). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV001266458	SCV001444633	pathogenic	Inborn genetic diseases	2018-04-23	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000005595	SCV001752508	pathogenic	Hermansky-Pudlak syndrome 1	2022-04-16	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000005595	SCV002025013	pathogenic	Hermansky-Pudlak syndrome 1	2019-09-28	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000614559	SCV002097054	pathogenic	Hermansky-Pudlak syndrome	2021-11-29	criteria provided, single submitter	curation	The p.His497fs variant in HPS1 has been reported in more than 10 individuals with Hermansky-Pudlak syndrome (PMID: 8896559, 20662851, 12442288, 9562579, 9497254) and has been identified in 0.03% (7/35412) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs281865163). 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#: 5277) and has been interpreted as Pathogenic by GeneReviews, Genetic Services Laboratory (University of Chicago), Clinical Molecular Genetics Laboratory (Johns Hopkins All Children's Hospital), Laboratory for Molecular Medicine (Partners HealthCare Personalized Medicine), Ambry Genetics, Invitae, EGL Genetic Diagnostics (Eurofins Clinical Diagnostics), GeneDx, OMIM, and Natera, Inc. In vitro functional studies provide some evidence that the p.His497fs variant may slightly impact protein function (PMID: 9345105). 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 497 and leads to a premature termination codon 90 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, PS3_moderate, PVS1 (Richards 2015).
Baylor Genetics	RCV000005595	SCV004199912	pathogenic	Hermansky-Pudlak syndrome 1	2023-10-30	criteria provided, single submitter	clinical testing
OMIM	RCV000005595	SCV000025777	pathogenic	Hermansky-Pudlak syndrome 1	1998-04-30	no assertion criteria provided	literature only
GeneReviews	RCV000005595	SCV000054519	not provided	Hermansky-Pudlak syndrome 1		no assertion provided	literature only
Natera, Inc.	RCV000614559	SCV001455561	pathogenic	Hermansky-Pudlak syndrome	2020-09-16	no assertion criteria provided	clinical testing
Genomics And Bioinformatics Analysis Resource, Columbia University	RCV000005595	SCV004024081	pathogenic	Hermansky-Pudlak syndrome 1		no assertion criteria provided	research