Submissions for variant NM_024747.6(HPS6):c.733C>T (p.Arg245Ter)

dbSNP: rs2136334244

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001919524	SCV002193099	pathogenic	not provided	2022-09-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg245*) in the HPS6 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 531 amino acid(s) of the HPS6 protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with HPS6-related conditions. ClinVar contains an entry for this variant (Variation ID: 1422405). This variant disrupts a region of the HPS6 protein in which other variant(s) (p.Gln305*) have been determined to be pathogenic (PMID: 19843503; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226503	SCV003923196	likely pathogenic	Hermansky-Pudlak syndrome	2023-03-03	criteria provided, single submitter	clinical testing	Variant summary: HPS6 c.733C>T (p.Arg245X) results in a premature termination codon that is not expected to cause nonsense mediated decay (NMD), but is predicted to cause a truncation, removing a large part of the 775 amino acid long protein (InterPro). Truncations downstream of this position have been reported in affected individuals (HGMD). The variant was absent in 250588 control chromosomes (gnomAD). To our knowledge, no occurrence of c.733C>T in individuals affected with Hermansky-Pudlak Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One submitter has provided a clinical-significance assessment for this variant to ClinVar after 2014, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.