Submissions for variant NM_001042702.5(PJVK):c.961_964dup (p.Val322fs)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV003237205	SCV003935785	uncertain significance	not provided	2022-12-21	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation as the last 31 amino acids are replaced with 10 different amino acids, although loss-of-function variants have not been reported downstream of this position in the protein; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV003237205	SCV004274406	pathogenic	not provided	2023-12-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Val322Aspfs*11) in the DFNB59 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 31 amino acid(s) of the DFNB59 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 DFNB59-related conditions. ClinVar contains an entry for this variant (Variation ID: 2506836). This variant disrupts a region of the DFNB59 protein in which other variant(s) (p.Cys343Ser) have been determined to be pathogenic (PMID: 22617256, 35052489). 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.