Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000481014 | SCV000566641 | uncertain significance | not provided | 2017-12-06 | criteria provided, single submitter | clinical testing | This variant is denoted SMAD4 c.1002G>T at the cDNA level, p.Gln334His (Q334H) at the protein level, and results in the change of a Glutamine to a Histidine (CAG>CAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. SMAD4 Gln334His was not observed in large population cohorts (Lek 2016). Since Glutamine and Histidine differ in some properties, this is considered a semi-conservative amino acid substitution. SMAD4 Gln334His is located in the MH2 domain (UniProt). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available evidence, it is unclear whether SMAD4 Gln334His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. |
Invitae | RCV000701948 | SCV000830774 | uncertain significance | Juvenile polyposis syndrome | 2023-12-09 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 334 of the SMAD4 protein (p.Gln334His). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SMAD4-related conditions. ClinVar contains an entry for this variant (Variation ID: 419077). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SMAD4 protein function. 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. |
Ambry Genetics | RCV002395147 | SCV002696673 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome | 2019-11-14 | criteria provided, single submitter | clinical testing | The p.Q334H variant (also known as c.1002G>T), located in coding exon 8 of the SMAD4 gene, results from a G to T substitution at nucleotide position 1002. The glutamine at codon 334 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |