ClinVar Miner

Submissions for variant NM_000195.5(HPS1):c.1096C>A (p.Pro366Thr)

gnomAD frequency: 0.00006  dbSNP: rs138771756
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
NIHR Bioresource Rare Diseases, University of Cambridge RCV000851655 SCV000899423 likely pathogenic Hermansky-Pudlak syndrome 2019-02-01 criteria provided, single submitter research
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV000851655 SCV002097058 uncertain significance Hermansky-Pudlak syndrome 2021-11-29 criteria provided, single submitter curation The p.Pro366Thr variant in HPS1 has been reported in 1 individual with Hermansky-Pudlak syndrome (PMID: 31064749) and has been identified in 0.02% (4/24962) of African/African-American chromosomes by the Genome Aggregation Database (gnomAD,; dbSNP ID: rs748106098). 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#: 8626969) and has been interpreted as likely pathogenic by NIHR Bioresource Rare Diseases (University of Cambridge). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Pro366Thr variant is uncertain. ACMG/AMP Criteria applied: PM3_supporting, PP3 (Richards 2015).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002469283 SCV002765963 uncertain significance not specified 2022-11-04 criteria provided, single submitter clinical testing Variant summary: HPS1 c.1096C>A (p.Pro366Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251426 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1096C>A has been reported in the literature in an individual affected with a platelet function disorder who was a compound heterozygote with another pathogenic/likely pathogenic variant (Downes_2019). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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