ClinVar Miner

Submissions for variant NM_001377.3(DYNC2H1):c.5114T>C (p.Leu1705Pro) (rs878854166)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000234493 SCV000285825 uncertain significance Jeune thoracic dystrophy 2016-01-20 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 1705 of the DYNC2H1 protein (p.Leu1705Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a DYNC2H1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
GeneDx RCV000487201 SCV000564951 likely pathogenic not provided 2017-03-16 criteria provided, single submitter clinical testing The L1705P variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge; however, it has been observed at GeneDx in trans with another expected pathogenic variant in two affected siblings with clinical features of a DYNC2H1-related disorder. In addition, it has also been observed in two fetal demise siblings in the presence of another expected pathogenic variant in trans. The L1705P variant is not observed in large population cohorts (Lek et al., 2016; Exome Variant Server). L1705P is a semi- conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, this variant is interpreted as likely pathogenic.

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