Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001039027 | SCV001202533 | uncertain significance | Juvenile polyposis syndrome | 2022-10-07 | 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects SMAD4 function (PMID: 15637079, 29955155). 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. ClinVar contains an entry for this variant (Variation ID: 837644). This variant has not been reported in the literature in individuals affected with SMAD4-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 159 of the SMAD4 protein (p.Lys159Arg). |
| Ambry Genetics | RCV002337107 | SCV002638654 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome | 2019-12-18 | criteria provided, single submitter | clinical testing | The p.K159R variant (also known as c.476A>G), located in coding exon 4 of the SMAD4 gene, results from an A to G substitution at nucleotide position 476. The lysine at codon 159 is replaced by arginine, an amino acid with highly similar properties. Several studies report reduced sumoylation with increased stability as well as increased transcriptional activity for this variant; however, it is unclear whether there is an association with disease (Lee PS et al. J. Biol. Chem., 2003 Jul;278:27853-63; Long J et al. Biochem. J., 2004 Apr;379:23-9; Chang CC et al. J. Biol. Chem., 2005 Mar;280:10164-73; Chang CC et al. Sci Rep, 2018 06;8:9786). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |