Submissions for variant NM_001005361.3(DNM2):c.1393C>T (p.Arg465Trp)

dbSNP: rs121909091

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000145902	SCV000193039	pathogenic	Centronuclear myopathy	2013-02-08	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000007704	SCV000245473	pathogenic	Autosomal dominant centronuclear myopathy	2013-11-06	criteria provided, single submitter	clinical testing	This variant has been previously reported as disease-causing and was found once in our laboratory in a 43-year-old male with centronuclear myopathy.
GeneDx	RCV000373773	SCV000329337	pathogenic	not provided	2022-12-08	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that R465W increases GTPase activity and leads to a highly stable dynamin complex that is resistant to normal disassembly; knock-in mice show muscle defects, progressive atrophy, and muscle biopsy changes similar to humans (Cowling et al., 2011; Wang et al., 2010; Durieux et al., 2010); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26908122, 26199319, 27447704, 22369075, 16227997, 19623537, 20227276, 26633545, 22613877, 22451505, 22096584, 21762456, 21514436, 20529869, 28466468, 28740838, 19130742, 31017801, 31628461, 29246969, 32721234, 35282416, 33187981, 33097808, 35244154, 34595679, 35217605, 30291191, 32315611, 34463354, 20858595)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000641110	SCV000762732	pathogenic	Charcot-Marie-Tooth disease dominant intermediate B	2023-11-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 465 of the DNM2 protein (p.Arg465Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant centronuclear myopathy (PMID: 16227997, 22396310). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7281). 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: 20858595, 22096584, 22369075, 27343996). For these reasons, this variant has been classified as Pathogenic.
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001813964	SCV001755346	pathogenic	Abnormality of the musculature	2021-07-10	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000373773	SCV002021726	pathogenic	not provided	2023-09-25	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University Hospital Muenster	RCV000007704	SCV002496132	pathogenic	Autosomal dominant centronuclear myopathy	2022-02-04	criteria provided, single submitter	clinical testing	ACMG categories: PS3,PM1,PM2,PP3,PP5
MGZ Medical Genetics Center	RCV000007704	SCV002580826	pathogenic	Autosomal dominant centronuclear myopathy	2022-02-08	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV000145902	SCV004812566	pathogenic	Centronuclear myopathy	2024-04-07	criteria provided, single submitter	clinical testing	This sequence change in DNM2 is predicted to replace arginine with tryptophan at codon 465, p.(Arg465Trp). The arginine residue is highly conserved (100 vertebrates, Multiz Alignments), and is located in the dynamin central region. There is a large physicochemical difference between arginine and tryptophan. This variant is absent from the population database gnomAD v2.1 and v3.1. The variant is a commonly reported cause of centronuclear myopathy in different populations and segregates with disease in multiple families (PMID: 16227997, 22396310, 23394783, 26908122, 34837441). A knock-in mouse model for the variant develops myopathy (PMID: 20858595). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.83). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PP1_Strong, PP3, PS3_Moderate, PS4, PM2_Supporting.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000007704	SCV005091038	pathogenic	Autosomal dominant centronuclear myopathy	2023-09-25	criteria provided, single submitter	clinical testing	PM2, PP2, PP3, PP5 - The variant has been reported in ClinVar as Pathogenic by other laboratories (Variation ID 7281). This variant has been previously reported as causative for centronuclear myopathy. (PMID:34837441).
OMIM	RCV000007704	SCV000027905	pathogenic	Autosomal dominant centronuclear myopathy	2005-11-01	no assertion criteria provided	literature only
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000373773	SCV001798200	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000373773	SCV001928735	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000373773	SCV001956266	pathogenic	not provided		no assertion criteria provided	clinical testing
Inherited Neuropathy Consortium Ii, University Of Miami	RCV000641110	SCV004174654	uncertain significance	Charcot-Marie-Tooth disease dominant intermediate B	2016-01-06	no assertion criteria provided	literature only