Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV002010403 | SCV002290333 | uncertain significance | Developmental and epileptic encephalopathy, 31A | 2024-02-24 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 199 of the DNM1 protein (p.Arg199Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with DNM1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1499073). 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) performed at Invitae indicates that this missense variant is expected to disrupt DNM1 protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Neuberg Centre For Genomic Medicine, |
RCV002010403 | SCV005849441 | uncertain significance | Developmental and epileptic encephalopathy, 31A | criteria provided, single submitter | clinical testing | The missense c.595C>T (p.Arg199Cys) variant in DNM1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Arg199Cys variant is present with allele frequency of 0.001% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Uncertain Significance. Multiple lines of computational evidence (Polyphen - Probably Damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid at this position on DNM1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 199 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as a Variant of Uncertain Significance (VUS). |