Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002419212 | SCV002679760 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-05-31 | criteria provided, single submitter | clinical testing | The p.G267V variant (also known as c.800G>T), located in coding exon 4 of the SMARCA4 gene, results from a G to T substitution at nucleotide position 800. The glycine at codon 267 is replaced by valine, an amino acid with dissimilar properties. Missense and in-frame variants in SMARCA4 are known to cause neurodevelopmental disorders; however, such associations with rhabdoid tumor predisposition syndrome including small cell carcinoma of the ovary-hypercalcemic type (SCCOHT) are exceedingly rare (Kosho T et al. Am J Med Genet C Semin Med Genet. 2014 Sep;166C(3):262-75; Jelinic P et al. Nat Genet. 2014 May;46(5):424-6). 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. |
| Labcorp Genetics |
RCV003507431 | SCV004298003 | uncertain significance | Rhabdoid tumor predisposition syndrome 2 | 2023-08-30 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 267 of the SMARCA4 protein (p.Gly267Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Rhabdoid tumor predisposition syndrome (PMID: 28454995). ClinVar contains an entry for this variant (Variation ID: 1761639). 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 SMARCA4 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. |