Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Labcorp Genetics |
RCV001320666 | SCV001511461 | pathogenic | Rhabdoid tumor predisposition syndrome 2 | 2023-08-04 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. 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 expected to disrupt SMARCA4 protein function. ClinVar contains an entry for this variant (Variation ID: 1020994). This missense change has been observed in individual(s) with clinical features of Coffin-Siris syndrome (Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 549 of the SMARCA4 protein (p.Arg549Cys). |
Gene |
RCV001760403 | SCV001997913 | uncertain significance | not provided | 2023-10-19 | criteria provided, single submitter | clinical testing | Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 26743474) |
Genome- |
RCV001810027 | SCV002056442 | uncertain significance | Intellectual disability, autosomal dominant 16 | 2021-07-15 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV002395700 | SCV002704016 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-08-03 | criteria provided, single submitter | clinical testing | The p.R549C variant (also known as c.1645C>T), located in coding exon 9 of the SMARCA4 gene, results from a C to T substitution at nucleotide position 1645. The arginine at codon 549 is replaced by cysteine, an amino acid with highly dissimilar 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. 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). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |