Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Broad Center for Mendelian Genomics, |
RCV001829294 | SCV002097060 | likely pathogenic | Hermansky-Pudlak syndrome | 2021-11-29 | criteria provided, single submitter | curation | The p.Gly321fs variant in HPS1 has been reported in 1 individual, in the compound heterozygous state, with Hermansky-Pudlak syndrome (PMID: 9497254), and has been identified in 0.006% (1/15402) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs606231156). 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#: 21110) and has been interpreted as pathogenic by GeneReviews. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 321 and leads to a premature termination codon 10 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: PM3_supporting, PM2_supporting, PVS1 (Richards 2015). |
| Invitae | RCV002034692 | SCV002228196 | pathogenic | not provided | 2021-07-06 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Gly321Alafs*10) 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 not present in population databases (ExAC no frequency). ClinVar contains an entry for this variant (Variation ID: 21110). This variant is also known as G321delG. This premature translational stop signal has been observed in individual(s) with Hermansky-Pudlak syndrome (PMID: 9497254). |
| Baylor Genetics | RCV003475105 | SCV004199930 | pathogenic | Hermansky-Pudlak syndrome 1 | 2023-09-14 | criteria provided, single submitter | clinical testing |