Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000799051 | SCV000938698 | uncertain significance | Dilated cardiomyopathy 1CC; Hypertrophic cardiomyopathy 20 | 2023-12-23 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 286 of the NEXN protein (p.Arg286Gln). This variant is present in population databases (no rsID available, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with NEXN-related conditions. ClinVar contains an entry for this variant (Variation ID: 645036). 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 not expected to disrupt NEXN protein function with a negative 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. |
| Victorian Clinical Genetics Services, |
RCV002470986 | SCV002768685 | uncertain significance | Dilated cardiomyopathy 1CC | 2020-06-11 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 3C-VUS. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine (exon 8). (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (3 heterozygotes, 0 homozygotes). (P) 0309 - An alternative amino acid change at the same position to tryptophan has been observed in gnomAD (35 heterozygotes, 0 homozygotes). (N) 0503 - Missense variant consistently predicted to be tolerated or not conserved in mammals with a minor amino acid change. (B) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (N) 0710 - Comparable variants have some previous evidence for being benign. A different variant in the same codon resulting in a change to a tryptophan has been reported as a VUS but more recently as likely benign (ClinVar, PMID: 28798025). (B) 0804 - Variant has previously been described as variant of uncertain significance in ClinVar. (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign |
| Fulgent Genetics, |
RCV000799051 | SCV002785900 | uncertain significance | Dilated cardiomyopathy 1CC; Hypertrophic cardiomyopathy 20 | 2021-10-12 | criteria provided, single submitter | clinical testing |