Submissions for variant NM_001005361.3(DNM2):c.1852G>A (p.Ala618Thr)

dbSNP: rs773598203

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Congenital Myopathies Variant Curation Expert Panel, ClinGen	RCV004732482	SCV005367881	pathogenic	Centronuclear myopathy	2024-08-07	reviewed by expert panel	curation	The c.1852G>A (p.Ala618Thr) variant in DNM2 is a missense variant predicted to cause substitution of Alanine by Threonine at amino acid 618. This variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.818, which is above the threshold of 0.7, evidence that correlates with impact to DNM2 function (PP3). DNM2, in which the variant was identified, is defined by the ClinGen Congenital Myopathies VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant has been reported in four probands with features of centronuclear myopathy, two of which were de novo with parental relationships confirmed (PS4, PS2; PMIDs:17932957, 28357410, 34463354, 32154989). In vitro assays showed an increase in GTPase activity and oligomer stability indicating that this variant impacts protein function (PMIDs: 26199319, 20700106, 34744632)(PS3_Moderate). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant centronuclear myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PS4, PS2, PS3_Moderate, PM2_Supporting, PP2, PP3 (ClinGen Congenital Myopathies VCEP specifications version 1; 8/7/2024).
GeneDx	RCV000520544	SCV000617317	pathogenic	not provided	2018-05-18	criteria provided, single submitter	clinical testing	The A618T pathogenic variant has been previously reported in patients with centronuclear myopathy (Bitoun et al., 2007; Susman et al., 2010). Functional studies demonstrate A618T is a gain-of-function variant which leads to T-tubule fragmentation (Chin et al., 2015). The A618T variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The A618T 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. Additionally, this substitution occurs at a position that is conserved across species, and missense variants in the same residue (A618D) and in nearby residues (D614N; S619L/W; L621P) have been reported in the Human Gene Mutation Database in association with centronuclear myopathy (Stenson et al., 2014), supporting the functional importance of this region of the protein. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, we interpret A618T as a pathogenic variant, and it's presence is consistent with a diagnosis of a DNM2-related disorder.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001384482	SCV001583991	pathogenic	Charcot-Marie-Tooth disease dominant intermediate B	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 618 of the DNM2 protein (p.Ala618Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with DNM2-related conditions (PMID: 17932957, 28357410). In at least one individual the variant was observed to be de novo. This variant is also known as c.1840G>A (p.Ala614Thr). ClinVar contains an entry for this variant (Variation ID: 449326). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DNM2 protein function. Experimental studies have shown that this missense change affects DNM2 function (PMID: 20529869, 20700106, 26199319). This variant disrupts the p.Ala618 amino acid residue in DNM2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19932619; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000520544	SCV003823312	pathogenic	not provided	2022-08-04	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004787830	SCV005400633	pathogenic	Autosomal dominant centronuclear myopathy	2024-10-10	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with centronuclear myopathy (MIM#1160150). Charcot-Marie-Tooth disease, axonal type 2M and dominant intermediate B (MIM#606482) are also associated with this gene; currently the mechanism of disease for these conditions is not established. (I) 0107 - This gene is associated with autosomal dominant disease. DNM2 is generally associated with autosomal dominant disease, however recessive inheritance of a hypomorphic allele has been reported in a family where homozygote missense offspring displayed a severe lethal neonatal phenotype, and the carrier parents presented with a mild form of myopathy (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity. Interfamilial and intrafamilial variability has been reported (PMID: 22396310). (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to threonine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (v2, v3 and v4). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v4: 7 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and high conservation. (I) 0600 - Variant is located in the annotated PH Domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported three times as pathogenic in ClinVar by clinical laboratories. This variant has been reported in families and individuals with centronuclear myopathy (PMIDs: 22396310, 17932957, 20227276). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Transfected C25 myoblasts with the p.(Ala218Thr) variant displayed markedly reduced exocytosis and altered fusion pore dynamics. This is consistent with previous findings in well-known CNM-associated pathogenic variants which impair GLUT-4 insertion into myoblast plasmalemma (PMID: 36142275). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Inherited Neuropathy Consortium Ii, University Of Miami	RCV001384482	SCV004174721	uncertain significance	Charcot-Marie-Tooth disease dominant intermediate B	2016-01-06	no assertion criteria provided	literature only