ClinVar Miner

Submissions for variant NM_001377.3(DYNC2H1):c.12439C>T (p.Arg4147Cys) (rs755441612)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Dan Cohn Lab,University Of California Los Angeles RCV000515950 SCV000611966 pathogenic Short-rib polydactyly syndrome type III 2017-06-01 no assertion criteria provided research
GeneDx RCV000428176 SCV000529806 uncertain significance not provided 2016-07-21 criteria provided, single submitter clinical testing The R4154C variant in the DYNC2H1 has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant was not observed in approximately 6000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R4154C 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. We interpret R4154C as a variant of uncertain significance.
Invitae RCV000704632 SCV000833588 uncertain significance Jeune thoracic dystrophy 2018-03-15 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 4154 of the DYNC2H1 protein (p.Arg4154Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs755441612, ExAC 0.006%). This variant has been reported in combination with a second DYNC2H1 variant in an individual affected with short-rib polydactyly syndrome, type III  (PMID: 29068549). ClinVar contains an entry for this variant (Variation ID: 387691). 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 and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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