ClinVar Miner

Submissions for variant NM_001377.3(DYNC2H1):c.10322T>C (p.Leu3441Pro)

gnomAD frequency: 0.00007  dbSNP: rs771487311
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000408623 SCV000484421 likely pathogenic Asphyxiating thoracic dystrophy 3 2014-07-11 criteria provided, single submitter clinical testing This substitution is predicted to create a change of a leucine to a proline at amino acid position 3448, NP_001073932.1(DYNC2H1): p.Leu3448). The leucine at this position is highly conserved and is located in the ATP-binding dynein motor region D5.Grantham assessment is likely deleterious due to conservation and amino acid properties. In-silico software predicts this variant to be disease-causing. This is a novel variant not present in disease or population databases. It was identified in a patient with clinical and radiographic features of JATD, and a second novel missense variant in teh DYNC2H1 gene was present in trans.
GeneDx RCV001805030 SCV002526657 likely pathogenic not provided 2023-07-17 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34040173, 26938784, 28832562, 24183451, 29068549, 29453417, 27535533, 36442996, Buchh2023[Abstract])
Labcorp Genetics (formerly Invitae), Labcorp RCV000515875 SCV004353319 pathogenic Jeune thoracic dystrophy 2024-02-06 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 3448 of the DYNC2H1 protein (p.Leu3448Pro). This variant is present in population databases (rs771487311, gnomAD 0.005%). This missense change has been observed in individual(s) with DYNC2H1-related conditions (PMID: 24183451, 26938784, 29068549). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 369661). 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%. For these reasons, this variant has been classified as Pathogenic.
Dan Cohn Lab, University Of California Los Angeles RCV000516064 SCV000611910 pathogenic Short-rib thoracic dysplasia 6 with or without polydactyly 2017-06-01 no assertion criteria provided research
Dan Cohn Lab, University Of California Los Angeles RCV000408623 SCV000611928 pathogenic Asphyxiating thoracic dystrophy 3 2017-06-01 no assertion criteria provided research
Dan Cohn Lab, University Of California Los Angeles RCV000515875 SCV000611991 pathogenic Jeune thoracic dystrophy 2017-06-01 no assertion criteria provided research
University of Washington Center for Mendelian Genomics, University of Washington RCV000515875 SCV001479725 likely pathogenic Jeune thoracic dystrophy no assertion criteria provided research
University of Washington Center for Mendelian Genomics, University of Washington RCV000516064 SCV001479867 likely pathogenic Short-rib thoracic dysplasia 6 with or without polydactyly no assertion criteria provided research
University of Washington Center for Mendelian Genomics, University of Washington RCV000408623 SCV001479881 likely pathogenic Asphyxiating thoracic dystrophy 3 no assertion criteria provided research
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000408623 SCV001548282 uncertain significance Asphyxiating thoracic dystrophy 3 flagged submission research
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center RCV001805030 SCV002051589 uncertain significance not provided 2021-02-17 flagged submission clinical testing PM2

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