ClinVar Miner

Submissions for variant NM_000195.5(HPS1):c.1858-1G>A

gnomAD frequency: 0.00001  dbSNP: rs758797992
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV001829300 SCV002097085 pathogenic Hermansky-Pudlak syndrome 2021-11-29 criteria provided, single submitter curation The c.1858-1G>A variant in HPS1 has been reported in 1 individual, in the homozygous state, with Hermansky-Pudlak syndrome (PMID: 31898847) and has been identified in 0.002% (2/110986) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs758797992). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant is located in the 5' splice region. Computational tools predict a splicing impact, though this information is not predictive enough to determine pathogenicity. 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: PVS1, PM2_supporting, PM3_supporting (Richards 2015).
Invitae RCV002034693 SCV002277071 likely pathogenic not provided 2024-01-17 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 18 of the HPS1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in HPS1 are known to be pathogenic (PMID: 12442288, 16185271). This variant is present in population databases (rs758797992, gnomAD 0.002%). Disruption of this splice site has been observed in individual(s) with Hermansky-Pudlak syndrome (PMID: 31898847). ClinVar contains an entry for this variant (Variation ID: 1341386). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx RCV002034693 SCV003921690 pathogenic not provided 2023-05-01 criteria provided, single submitter clinical testing Observed in apparent homozygous state in a patient reported to have Hermansky-Pudlak syndrome in the literature (Huizing et al., 2020) and not observed in homozygous state in controls, however, patient-specific clinical information was not provided; Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31898847)
Baylor Genetics RCV003470938 SCV004199915 pathogenic Hermansky-Pudlak syndrome 1 2023-10-25 criteria provided, single submitter clinical testing

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