ClinVar Miner

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

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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
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 2017-06-01 criteria provided, single submitter clinical testing The c.1472_1487dup16 pathogenic variant in the HPS1 gene has been reported previously in association with Hermansky-Pudluk syndrome, and is considered a founder mutation among the population of Northwestern Puerto Rico (Oh et al., 1996). The c.1472_1487dup16 variant causes a frameshift starting with codon Histidine 497, changes this amino acid to a Glutamine residue, and creates a premature Stop codon at position 90 of the new reading frame, denoted p.His497GlnfsX90. This variant results in nonsense mediated mRNA decay (Hazelwood et al., 1997). The c.1472_1487dup16 variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. However, the 1000 Genomes Database reports c.1472_1487dup16 was observed in 3/208 (1.44%) alleles from individuals of Puerto Rican background (McVean et al., 2012). Therefore, the c.1472_1487dup16 variant is pathogenic.
GeneReviews RCV000005595 SCV000054519 pathologic Hermansky-Pudlak syndrome 1 2012-10-11 no assertion criteria provided curation Converted during submission to Pathogenic.
Genetic Services Laboratory, University of Chicago RCV000005595 SCV000595166 pathogenic Hermansky-Pudlak syndrome 1 2015-10-14 criteria provided, single submitter clinical testing
Invitae RCV000482079 SCV000959691 pathogenic not provided 2018-11-28 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.
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 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).
OMIM RCV000005595 SCV000025777 pathogenic Hermansky-Pudlak syndrome 1 1998-04-30 no assertion criteria provided literature only

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