ClinVar Miner

Submissions for variant NM_000195.5(HPS1):c.1472_1487dup (p.His497fs) (rs281865163)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics 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, Partners HealthCare 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; 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 2020-10-19 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. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported to be homozygous in many individuals affected with Hermansky-Pudlak syndrome, and is considered a founder variant in the Puerto Rican population (PMID: 8896559, 9562579, 20662851) Loss-of-function variants in HPS1 are known to be pathogenic (PMID: 12442288, 16185271). 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 2021-06-30 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 pathologic Hermansky-Pudlak syndrome 1 2012-10-11 no assertion criteria provided curation Converted during submission to Pathogenic.
Natera, Inc. RCV000614559 SCV001455561 pathogenic Hermansky-Pudlak syndrome 2020-09-16 no assertion criteria provided clinical testing

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