Submissions for variant NM_001376.5(DYNC1H1):c.751C>G (p.Arg251Gly) (rs879253979)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000235525	SCV000293041	uncertain significance	not specified	2016-04-28	criteria provided, single submitter	clinical testing	The R251G variant has not been published as a pathogenic variant, 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 R251G 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. 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.
Invitae	RCV000797392	SCV000936946	uncertain significance	Charcot-Marie-Tooth disease, axonal, type 2O	2018-12-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with glycine at codon 251 of the DYNC1H1 protein (p.Arg251Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with DYNC1H1-related conditions. ClinVar contains an entry for this variant (Variation ID: 245868). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant disrupts the p.Arg251 amino acid residue in DYNC1H1. Another variant that disrupts this residue has been observed in individuals with DYNC1H1-related conditions (PMID: 26392352, Invitae), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. 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.