ClinVar Miner

Submissions for variant NM_000195.5(HPS1):c.1857+2T>C

gnomAD frequency: 0.00002  dbSNP: rs374689398
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
NIHR Bioresource Rare Diseases, University of Cambridge RCV000851934 SCV000899318 likely pathogenic Hermansky-Pudlak syndrome 2019-02-01 criteria provided, single submitter research
Labcorp Genetics (formerly Invitae), Labcorp RCV001215549 SCV001387300 likely pathogenic not provided 2023-11-12 criteria provided, single submitter clinical testing This sequence change affects a donor 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 (rs374689398, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with clinical features of Hermansky-Pudlak syndrome (PMID: 29941477, 31064749). ClinVar contains an entry for this variant (Variation ID: 627174). 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.
Fulgent Genetics, Fulgent Genetics RCV002493407 SCV002791318 pathogenic Hermansky-Pudlak syndrome 1 2024-03-11 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003413557 SCV004117515 likely pathogenic HPS1-related disorder 2023-06-26 criteria provided, single submitter clinical testing The HPS1 c.1857+2T>C variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported in the homozygous and compound heterozygous states in individuals with Hermansky-Pudlak syndrome (McElvaney et al. 2018. PubMed ID: 29941477; Table S3 in Downes et al. 2019. PubMed ID: 31064749). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Variants that disrupt the consensus splice donor site in HPS1 are expected to be pathogenic. Given the evidence, we interpret c.1857+2T>C as likely pathogenic.
Genetics and Molecular Pathology, SA Pathology RCV002493407 SCV004175352 pathogenic Hermansky-Pudlak syndrome 1 2021-11-26 criteria provided, single submitter clinical testing
Baylor Genetics RCV002493407 SCV004199929 pathogenic Hermansky-Pudlak syndrome 1 2024-02-14 criteria provided, single submitter clinical testing

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