ClinVar Miner

Submissions for variant NM_001377.3(DYNC2H1):c.12410C>G (p.Pro4137Arg) (rs761765709)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Dan Cohn Lab,University Of California Los Angeles RCV000228783 SCV000611938 pathogenic Jeune thoracic dystrophy 2017-06-01 no assertion criteria provided research
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000486569 SCV000232861 uncertain significance not provided 2015-05-04 criteria provided, single submitter clinical testing
GeneDx RCV000486569 SCV000574151 likely pathogenic not provided 2017-04-03 criteria provided, single submitter clinical testing The P4144R 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 two siblings with fetal demise in the presence of another likely pathogenic variant in trans. P4144R is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The P4144R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other 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.
Invitae RCV000228783 SCV000285823 uncertain significance Jeune thoracic dystrophy 2016-01-21 criteria provided, single submitter clinical testing This sequence change replaces proline with arginine at codon 4144 of the DYNC2H1 protein (p.Pro4144Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine. This variant is present in population databases (rs761765709, ExAC 0.003%) but has not been reported in the literature in individuals with a DYNC2H1-related disease. ClinVar contains an entry for this variant (Variation ID: 198962). 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 rare missense change with uncertain impact on protein function. There is no indication that this variant causes disease, but the evidence is insufficient at this time to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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