Submissions for variant NM_024747.6(HPS6):c.1999C>T (p.Arg667Ter)

gnomAD frequency: 0.00002  dbSNP: rs373272174

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002543012	SCV003486841	likely pathogenic	not provided	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg667*) in the HPS6 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 109 amino acid(s) of the HPS6 protein. This variant is present in population databases (rs373272174, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with Hermansky-Pudlak syndrome (PMID: 33878481). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 996365). This variant disrupts a region of the HPS6 protein in which other variant(s) (p.Leu731Serfs*28) have been observed in individuals with HPS6-related conditions (PMID: 31898847). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. 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.
Genetics and Prenatal Diagnosis Center, The First Affiliated Hospital of Zhengzhou University	RCV001290772	SCV001478883	likely pathogenic	Hermansky-Pudlak syndrome 6	2020-11-13	no assertion criteria provided	clinical testing