ClinVar Miner

Submissions for variant NM_001376.5(DYNC1H1):c.13286A>G (p.Gln4429Arg) (rs763724110)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236964 SCV000292923 uncertain significance not provided 2015-06-10 criteria provided, single submitter clinical testing The Q4429R variant has not been published as pathogenic, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 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 Q4429R variant 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. However, in silico analysis is inconsistent in its predictions as to whether or not the Q4429R variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic or a rare benign variant.
Invitae RCV000559833 SCV000651615 uncertain significance Charcot-Marie-Tooth disease, axonal, type 2O 2017-05-08 criteria provided, single submitter clinical testing This sequence change replaces glutamine with arginine at codon 4429 of the DYNC1H1 protein (p.Gln4429Arg). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and arginine. This variant is present in population databases (rs763724110, ExAC 0.01%) but has not been reported in the literature in individuals with a DYNC1H1-related disease. ClinVar contains an entry for this variant (Variation ID: 245792). 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 tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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