Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000230825 | SCV000289110 | pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2023-12-21 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 122 of the SMAD3 protein (p.Val122Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with SMAD3-related conditions (PMID: 30661052, 31915033; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 155836). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt SMAD3 function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. |
| Victorian Clinical Genetics Services, |
RCV002470771 | SCV002768986 | likely pathogenic | Aneurysm-osteoarthritis syndrome | 2022-03-31 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Loeys-Dietz syndrome 3 (MIM#613795). However, dominant negative is also a suggested mechanism for some missense variants (PMID: 30661052). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to methionine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated MH1 domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported as both likely pathogenic and as a VUS, and has been observed in two unrelated individuals with aortic disease (ClinVar, PMID: 31915033, PMID: 30661052). (I) 0903 - This variant has limited evidence for segregation with disease. This variant has segregated with disease in a single extended family with thoracic aortic dissection. The variant is absent in several unaffected relatives (PMID: 30661052, personal communication). (SP) 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 |
| Blueprint Genetics | RCV000143952 | SCV000188832 | likely pathogenic | Loeys-Dietz syndrome | 2013-11-12 | no assertion criteria provided | clinical testing |