ClinVar Miner

Submissions for variant NM_001376.5(DYNC1H1):c.10743A>C (p.Lys3581Asn) (rs768668529)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236114 SCV000294101 uncertain significance not provided 2016-03-31 criteria provided, single submitter clinical testing The K3581N variant has not been published as a pathogenic variant, nor has it been reported as a benign variant 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 K3581N 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, missense variants in nearby residues have not been reported in the Human Gene Mutation Database in association with DYNC1H1-related disorders (Stenson et al., 2014). In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000552491 SCV000651592 uncertain significance Charcot-Marie-Tooth disease, axonal, type 2O 2017-05-24 criteria provided, single submitter clinical testing This sequence change replaces lysine with asparagine at codon 3581 of the DYNC1H1 protein (p.Lys3581Asn). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and asparagine. This variant is present in population databases (rs768668529, ExAC 0.001%). This variant has not been reported in the literature in individuals with a DYNC1H1-related disease. ClinVar contains an entry for this variant (Variation ID: 246514). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). In summary, this variant has uncertain impact on DYNC1H1 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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