Submissions for variant NM_001376.5(DYNC1H1):c.4699C>T (p.Arg1567Trp)

dbSNP: rs377013246

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002018409	SCV002302755	likely pathogenic	Charcot-Marie-Tooth disease axonal type 2O	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1567 of the DYNC1H1 protein (p.Arg1567Trp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DYNC1H1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1513471). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DYNC1H1 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg1567 amino acid residue in DYNC1H1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23603762, 28196890, 31164858). This suggests that this residue is clinically significant, and that variants that disrupt this residue 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.
PreventionGenetics, part of Exact Sciences	RCV003911154	SCV004720455	uncertain significance	DYNC1H1-related disorder	2023-11-22	no assertion criteria provided	clinical testing	The DYNC1H1 c.4699C>T variant is predicted to result in the amino acid substitution p.Arg1567Trp. To our knowledge, this variant has not been reported in the literature in a large population database, indicating this variant is rare. A different missense variant affecting the same amino acid (p.Arg1567Gln) has been reported as pathogenic (Hoang et al. 2017. PubMed ID: 28196890; Poirier et al. 2013. PubMed ID: 23603762). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.