Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV002034173 | SCV002316259 | uncertain significance | not provided | 2023-06-05 | criteria provided, single submitter | clinical testing | 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. 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 SMAD2 protein function. ClinVar contains an entry for this variant (Variation ID: 1521943). This variant has not been reported in the literature in individuals affected with SMAD2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 462 of the SMAD2 protein (p.Arg462Cys). |
| Victorian Clinical Genetics Services, |
RCV002267644 | SCV002549769 | uncertain significance | Loeys-Dietz syndrome 6 | 2022-06-24 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with SMAD2-related connective tissue disorder (PMID: 29967133). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Rare examples of non-penetrance in Loeys-Dietz syndrome (LDS) have been documented, including somatic mosaicism (GeneReviews). (I) 0115 - Variants in this gene are known to have variable expressivity. Intrafamilial variability has been reported in LDS (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0601 - Variant is located in the well-established functional MH2 domain (PMID: 29967133). Mutagenesis studies have shown that Arg-462 is important for specific recognition and phosphorylation of the C-terminal serine residues of Smad2 by the type I TGFbeta receptor (PMID: 15210694). (SP) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. The p.(Arg462His) variant has been reported as a VUS in ClinVar. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |