Submissions for variant NM_001005360.2(DNM2):c.8A>G (p.Asn3Ser) (rs890297188)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000479544	SCV000574206	uncertain significance	not provided	2017-10-02	criteria provided, single submitter	clinical testing	The N3S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The N3S variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This 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, and in silico analysis predicts this variant is probably damaging to the protein structure/function.
Invitae	RCV000791747	SCV000931008	uncertain significance	Charcot-Marie-Tooth disease, dominant intermediate B	2018-11-13	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine with serine at codon 3 of the DNM2 protein (p.Asn3Ser). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and serine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has not been reported in the literature in individuals with DNM2-related disease. ClinVar contains an entry for this variant (Variation ID: 424401). 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: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.