Submissions for variant NM_001376.5(DYNC1H1):c.7138G>A (p.Ala2380Thr) (rs550161377)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000235243	SCV000293802	uncertain significance	not provided	2016-02-03	criteria provided, single submitter	clinical testing	The A2380T 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. Additionally, it was not observed with any significant frequency in the 1000 Genomes Project. The A2380T 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, Threonine is observed at this position in a distantly related 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.
Invitae	RCV000806855	SCV000946874	uncertain significance	Charcot-Marie-Tooth disease, axonal, type 2O	2018-08-09	criteria provided, single submitter	clinical testing	This sequence change replaces alanine with threonine at codon 2380 of the DYNC1H1 protein (p.Ala2380Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs550161377, ExAC 0.04%). This variant has not been reported in the literature in individuals with DYNC1H1-related disease. ClinVar contains an entry for this variant (Variation ID: 246307). 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"). 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.