Submissions for variant NM_001005360.2(DNM2):c.1852G>T (p.Ala618Ser) (rs773598203)

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Total submissions: 2

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000814094	SCV000954492	uncertain significance	Charcot-Marie-Tooth disease, dominant intermediate B	2018-09-21	criteria provided, single submitter	clinical testing	This sequence change replaces alanine with serine at codon 618 of the DNM2 protein (p.Ala618Ser). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and serine. This variant is present in population databases (rs773598203, ExAC 0.01%). This variant has not been reported in the literature in individuals with DNM2-related disease. 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: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). Variants that disrupt the p.Ala618 amino acid residue in DNM2 have been observed in affected individuals (PMID: 19932619, Invitae). This suggests that it is a clinically significant residue, and that other 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.
Centre for Mendelian Genomics,University Medical Centre Ljubljana	RCV001195893	SCV001366317	uncertain significance	Neuromuscular disorder	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2. This variant was detected in heterozygous state.

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