ClinVar Genomic variation as it relates to human health

The c.1856C>T variant in DNM2 is a missense variant predicted to cause substitution of serine by leucine at amino acid 619. This variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.936, 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 CM 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). The variant has been reported in at least four probands with centronuclear myopathy that was confirmed by muscle biopsy, one of which was a de novo occurrence with parental relationships confirmed (PMIDs: PMIDs:17932957, 30208955, 34595679, PS4, PS2). In vitro assays demonstrate that the p.S619L variant increases GTPase activity (PMID: 20700106), indicating that this variant impacts protein function. Additionally, a variant-specific zebrafish model (PMID: 23338057) and a variant-specific mouse model (PMID:32809972) recapitulate patient phenotypes of motor problems, early impaired muscle function and force, and myofiber hypotrophy (PS4). 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: PS2, PS4, PM2_Supporting, PP2, PP3. (Congenital Myopathies VCEP specifications version 1; 8/7/2024)

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 619 of the DNM2 protein (p.Ser619Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with centronuclear myopathy and is associated with severe neonatal hypotonia (PMID: 17932957, 20227276, 22396310). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 7285). 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: 20700106, 23338057, 24135484, 26199319). This variant disrupts the p.Ser619 amino acid residue in DNM2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17932957, 20700106, 22396310, 25957634). 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.