Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| NIHR Bioresource Rare Diseases, |
RCV000851655 | SCV000899423 | likely pathogenic | Hermansky-Pudlak syndrome | 2019-02-01 | criteria provided, single submitter | research | |
| Broad Center for Mendelian Genomics, |
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, http://gnomad.broadinstitute.org; 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, |
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. |