Submissions for variant NM_001005360.2(DNM2):c.1273C>A (p.Leu425Met) (rs879253980)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000235731	SCV000293053	uncertain significance	not provided	2015-08-27	criteria provided, single submitter	clinical testing	The L425M variant has not been published as pathogenic, 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 L425M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Leucine are tolerated across species. However, in silico analysis is inconsistent in its predictions as to whether or not the L425M 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	RCV000797726	SCV000937304	uncertain significance	Charcot-Marie-Tooth disease, dominant intermediate B	2019-05-03	criteria provided, single submitter	clinical testing	This sequence change replaces leucine with methionine at codon 425 of the DNM2 protein (p.Leu425Met). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with DNM2-related disease. ClinVar contains an entry for this variant (Variation ID: 245878). 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"). 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.