Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Broad Center for Mendelian Genomics, |
RCV000020872 | SCV003761113 | uncertain significance | Hermansky-Pudlak syndrome 4 | 2023-01-24 | criteria provided, single submitter | curation | The p.His154Arg variant in HPS4 has been reported in 3 individuals with Hermansky-Pudlak syndrome 4 (PMID: 12664304, 31898847), segregated with disease in 2 affected relatives from 2 families (PMID: 12664304, 31898847), and has been identified in 0.0009% (1/113688) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs281865098). 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. This variant has also been reported in ClinVar (Variation ID#: 21678) and has been interpreted as pathogenic by OMIM. Of the 3 affected individuals, 1 of those was a homozygote, which increases the likelihood that the p.His154Arg variant is pathogenic (PMID: 31898847). 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, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM3_supporting, PP1, PP3, PM2_supporting (Richards 2015). |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV004799749 | SCV005423411 | uncertain significance | not specified | 2024-10-04 | criteria provided, single submitter | clinical testing | Variant summary: HPS4 c.461A>G (p.His154Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251362 control chromosomes (gnomAD). c.461A>G has been reported in the literature in individuals affected with Hermansky-Pudlak Syndrome (Anderson_2003). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 12664304, 37647632). ClinVar contains an entry for this variant (Variation ID: 21678). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |
| OMIM | RCV000020872 | SCV000584193 | pathogenic | Hermansky-Pudlak syndrome 4 | 2003-07-01 | no assertion criteria provided | literature only |