Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000479880 | SCV000570528 | uncertain significance | not provided | 2016-06-02 | criteria provided, single submitter | clinical testing | This variant is denoted SMAD4 c.692G>C at the cDNA level, p.Gly231Ala (G231A) at the protein level, and results in the change of a Glycine to an Alanine (GGC>GCC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. SMAD4 Gly231Ala was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glycine and Alanine share similar properties, this is considered a conservative amino acid substitution. SMAD4 Gly231Ala occurs at a position where amino acids with properties similar to Glycine are tolerated across species and is not located in a known functional domain (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether SMAD4 Gly231Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. |
| Invitae | RCV002230936 | SCV000829550 | uncertain significance | Juvenile polyposis syndrome | 2023-06-30 | criteria provided, single submitter | clinical testing | This variant has not been reported in the literature in individuals affected with SMAD4-related conditions. 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 sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 231 of the SMAD4 protein (p.Gly231Ala). ClinVar contains an entry for this variant (Variation ID: 421348). 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 SMAD4 protein function. |
| Ambry Genetics | RCV003168958 | SCV003863695 | likely benign | Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome | 2022-12-23 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. |