ClinVar Miner

Submissions for variant NM_001377.3(DYNC2H1):c.12831G>T (p.Arg4277Ser)

dbSNP: rs372878677
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues RCV000853584 SCV000996551 likely pathogenic Asphyxiating thoracic dystrophy 3 2019-04-08 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV005092534 SCV005773205 likely pathogenic Jeune thoracic dystrophy 2024-02-11 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 4284 of the DYNC2H1 protein (p.Arg4284Ser). This variant is present in population databases (rs372878677, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with DYNC2H1-related conditions. ClinVar contains an entry for this variant (Variation ID: 692242). 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 DYNC2H1 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg4284 amino acid residue in DYNC2H1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 29068549). 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.

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