Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001302691 | SCV001491909 | uncertain significance | Rhabdoid tumor predisposition syndrome 2 | 2020-08-20 | criteria provided, single submitter | clinical testing | This variant has been observed in individual(s) with clinical features of Coffin-Siris syndrome (PMID: 28990276). 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 missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C55"). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with lysine at codon 1515 of the SMARCA4 protein (p.Glu1515Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. |
| Ambry Genetics | RCV002327656 | SCV002634183 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-08-14 | criteria provided, single submitter | clinical testing | The p.E1515K variant (also known as c.4543G>A), located in coding exon 31 of the SMARCA4 gene, results from a G to A substitution at nucleotide position 4543. The glutamic acid at codon 1515 is replaced by lysine, an amino acid with similar properties. This variant was detected by whole exome sequencing in an individual with some features of Coffin-Siris syndrome (Zhao JJ et al. Am J Med Genet B Neuropsychiatr Genet, 2018 Jan;177:10-20). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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. |