Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Broad Center for Mendelian Genomics, |
RCV001829297 | SCV002097067 | uncertain significance | Hermansky-Pudlak syndrome | 2021-11-29 | criteria provided, single submitter | curation | The p.Arg106Gly variant in HPS1 has been reported in 1 individual, in the compound heterozygous state, with Hermansky-Pudlak syndrome (PMID: 31141302), and has been identified in 0.008% (2/24946) of African/African-American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs376557022). 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. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Arg106Gly variant is uncertain. ACMG/AMP Criteria applied: PM2_supporting, PM3 (Richards 2015). |
| Labcorp Genetics |
RCV002542780 | SCV003439652 | likely pathogenic | not provided | 2022-10-12 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 106 of the HPS1 protein (p.Arg106Gly). This variant is present in population databases (rs376557022, gnomAD 0.008%). This missense change has been observed in individual(s) with Hermansky-Pudlak syndrome (PMID: 27593200). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1341383). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on HPS1 protein function. 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. |