Submissions for variant NM_004945.3(DNM2):c.1597G>A (p.Gly533Ser) (rs121909093)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000235229	SCV000293785	likely pathogenic	not provided	2018-02-28	criteria provided, single submitter	clinical testing	A variant that is likely pathogenic has been identified in the DNM2 gene. The G537S variant has notbeen published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge.The G537S variant is not observed in large population cohorts (Lek et al., 2016; 1000 GenomesConsortium et al., 2015; Exome Variant Server). The G537S variant is a non-conservative amino acidsubstitution, 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 acrossspecies. In silico analysis predicts this variant is probably damaging to the protein structure/function.Additionally, a different amino acid substitution at the same position (G573C) and another missensevariant in a nearby residue have been reported in the Human Gene Mutation Database in associationwith DNM2-related disorders (Stenson et al., 2014), supporting the functional importance of thisregion of the protein. Therefore, this variant is likely pathogenic; however, the possibility that it isbenign cannot be excluded.
Centre for Mendelian Genomics,University Medical Centre Ljubljana	RCV000415354	SCV000492700	likely pathogenic	Sensorimotor neuropathy	2015-08-05	criteria provided, single submitter	clinical testing
Invitae	RCV000641104	SCV000762726	pathogenic	Charcot-Marie-Tooth disease, dominant intermediate B	2020-01-07	criteria provided, single submitter	clinical testing	This sequence change replaces glycine with serine at codon 537 of the DNM2 protein (p.Gly537Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 30373780, Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 246295). 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"). This variant disrupts the p.Gly537 amino acid residue in DNM2. Other variant(s) that disrupt this residue have been observed in individuals with DNM2-related conditions (PMID: 17636067), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000235229	SCV001371621	likely pathogenic	not provided	2020-06-01	criteria provided, single submitter	clinical testing