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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