Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV001583810 | SCV001820167 | uncertain significance | not provided | 2023-02-01 | criteria provided, single submitter | clinical testing | Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge |
| Labcorp Genetics |
RCV001866174 | SCV002299092 | uncertain significance | Congenital contractural arachnodactyly | 2021-10-06 | 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 FBN2 protein function. This variant has not been reported in the literature in individuals affected with FBN2-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces tyrosine with serine at codon 2894 of the FBN2 protein (p.Tyr2894Ser). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and serine. |
| Victorian Clinical Genetics Services, |
RCV001866174 | SCV005086474 | uncertain significance | Congenital contractural arachnodactyly | 2023-07-17 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. However, dominant negative is a likely mechanism of disease (PMID: 31316167). (I) 0107 - This gene is associated with autosomal dominant disease. There are also rare reports of a severe form of congenital contractural arachnodactyly due to biallelic variants (PMID: 33571691). (I) 0115 - Variants in this gene are known to have variable expressivity. Intrafamilial and interfamilial variability is well reported for this gene (PMID: 20301560). (I) 0200 - Variant is predicted to result in a missense amino acid change from tyrosine to serine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (p.(Tyr2894Cys): 1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. The p.(Tyr2894Cys) variant has been classified as a VUS by one clinical diagnostic laboratory (ClinVar). (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been classified as a VUS by two clinical diagnostic laboratories (ClinVar). (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) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |