Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001214312 | SCV001385987 | pathogenic | not provided | 2025-01-23 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Ser285Alafs*46) in the HPS1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HPS1 are known to be pathogenic (PMID: 12442288, 16185271). This variant is present in population databases (rs757883936, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with HPS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 944005). For these reasons, this variant has been classified as Pathogenic. |
| Broad Center for Mendelian Genomics, |
RCV001828706 | SCV002097071 | likely pathogenic | Hermansky-Pudlak syndrome | 2021-12-10 | criteria provided, single submitter | curation | The p.Ser285fs variant in HPS1 has not been previously reported in individuals with Hermansky-Pudlak syndrome but has been identified in 0.007% (2/30614) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs757883936). 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. It is of note that this variant occurs in a homopolymer repeat, which could indicate that it exists as an artifact from sequencing. However, disease-causing variants have been reported in homopolymer regions, so this is not enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID#: 944005) and has been interpreted as pathogenic by Invitae. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 285 and leads to a premature termination codon 46 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the HPS1 gene is an established disease mechanism in autosomal recessive Hermansky-Pudlak syndrome. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive Hermansky-Pudlak syndrome. ACMG/AMP Criteria applied: PVS1, PM2 (Richards 2015). |
| Baylor Genetics | RCV003469361 | SCV004199923 | likely pathogenic | Hermansky-Pudlak syndrome 1 | 2023-10-07 | criteria provided, single submitter | clinical testing |