Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV001222721 | SCV001394837 | uncertain significance | Rhabdoid tumor predisposition syndrome 2 | 2023-08-27 | criteria provided, single submitter | clinical testing | This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 1543 of the SMARCA4 protein (p.Lys1543Arg). This variant is not present in population databases (gnomAD no frequency). 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 950907). This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. |
Ambry Genetics | RCV002339589 | SCV002639172 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-04-13 | criteria provided, single submitter | clinical testing | The p.K1543R variant (also known as c.4628A>G), located in coding exon 31 of the SMARCA4 gene, results from an A to G substitution at nucleotide position 4628. The lysine at codon 1543 is replaced by arginine, 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 tolerated 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). Based on the supporting evidence, the association of this alteration with Coffin-Siris syndrome is unknown; however, the association of this alteration with rhabdoid tumor predisposition syndrome is unlikely. |