ClinVar Miner

Submissions for variant NM_001376.5(DYNC1H1):c.10574G>A (p.Arg3525His)

dbSNP: rs2152592202
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001555570 SCV001777011 pathogenic not provided 2022-01-22 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31278258, 31785789, 26100331, 25609763, 25512093)
Labcorp Genetics (formerly Invitae), Labcorp RCV002032609 SCV002271746 likely pathogenic Charcot-Marie-Tooth disease axonal type 2O 2020-12-07 criteria provided, single submitter clinical testing This variant is not present in population databases (ExAC no frequency). 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. This variant disrupts the p.Arg3525 amino acid residue in DYNC1H1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28554332). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. This variant has been observed in individual(s) with clinical features of DYNC1H1-related conditions (PMID: 31278258). This sequence change replaces arginine with histidine at codon 3525 of the DYNC1H1 protein (p.Arg3525His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine.

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