ClinVar Genomic variation as it relates to human health

The variant NM_001005361.3:c.1393C>T in DNM2 is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 465 (p.Arg465Trp). The highest population minor allele frequency in gnomAD v4.1 is 0.000001695 (2/1180018 alleles) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). The REVEL computational prediction analysis tool produced a score of 0.83, which is above the threshold necessary to apply PP3. This variant has been reported in at least six probands with confirmed centronuclear myopathy (PS4; PMID: 16227997, 19130742, 22613877, 26908122, 28740838, 34463354, 34595679). In addition, it segregated in five affected individuals in one family (PP1_Strong; PMID: 16227997). Functional studies have demonstrated that this variant increases GTPase activity compared to wildtype dynamin (PMIDs: 20529869, 26199319). Several knock-in mouse models with the variant have been created and show muscle defects, progressive atrophy and morphological abnormalities similar to those observed in human biopsies, and DNM2 reduction has been shown to rescue the phenotype in mice (PS3; PMIDs: 20858595, 30291191). 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: PP3, PS4, PP1_Strong, PS3. (ClinGen Congenital Myopathies VCEP specifications version 1; 8/7/2024)

ACMG categories: PS3,PM1,PM2,PP3,PP5

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.

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)

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.

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.

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).

PP3, PM2_moderate, PM6, PS3, PS4

The DNM2 c.1393C>T variant is predicted to result in the amino acid substitution p.Arg465Trp. This is one of the most common variants reported to be causative for autosomal dominant centronuclear myopathy (see, for example, Bitoun et al 2005. PubMed ID: 16227997; Cowling et al 2011. PubMed ID: 21514436; Koutsopoulos et al 2011. PubMed ID: 22096584). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.