Submissions for variant NM_001376.5(DYNC1H1):c.6421G>A (p.Val2141Ile) (rs765613848)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000463690	SCV000548838	uncertain significance	Charcot-Marie-Tooth disease, axonal, type 2O	2016-11-08	criteria provided, single submitter	clinical testing	This sequence change replaces valine with isoleucine at codon 2141 of the DYNC1H1 protein (p.Val2141Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs765613848, ExAC 0.009%) but has not been reported in the literature in individuals with a DYNC1H1-related disease. 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: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). In summary, this variant is a rare missense change with uncertain impact on 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.
GeneDx	RCV000498549	SCV000590300	uncertain significance	not provided	2017-06-26	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the DYNC1H1 gene. The V2141I variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The V2141I variant is observed in 1/11576 (0.01%) alleles from individuals of Latino background and in 1/66680 (0.001%) alleles from individuals of European background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The V2141I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species. 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.