ClinVar Miner

Submissions for variant NM_022081.6(HPS4):c.1546C>T (p.Gln516Ter)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV002789957 SCV003761106 uncertain significance Hermansky-Pudlak syndrome 4 2023-01-24 criteria provided, single submitter curation The p.Gln516Ter variant in HPS4 has been reported in 1 individual, in the compound heterozygous state, with Hermansky-Pudlak syndrome 4 (PMID: 31898847) and has been identified in 0.002% (2/113762) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs372833027). 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 nonsense variant leads to a premature termination codon at position 516, which is predicted to lead to a truncated or absent protein. Loss of function of the HPS4 gene is strongly associated to autosomal recessive Hermansky-Pudlak syndrome 4. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PVS1_strong, PM2_supporting (Richards 2015).
Labcorp Genetics (formerly Invitae), Labcorp RCV003108234 SCV003782828 pathogenic not provided 2023-07-15 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln516*) in the HPS4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HPS4 are known to be pathogenic (PMID: 12664304). This variant is present in population databases (rs372833027, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with Hermansky–Pudlak syndrome (PMID: 31898847). ClinVar contains an entry for this variant (Variation ID: 2412666). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV002789957 SCV005059733 pathogenic Hermansky-Pudlak syndrome 4 2024-02-17 criteria provided, single submitter clinical testing

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