ClinVar Miner

Submissions for variant NM_003072.5(SMARCA4):c.1095G>C (p.Glu365Asp)

dbSNP: rs2145822205
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001366271 SCV001562570 uncertain significance Rhabdoid tumor predisposition syndrome 2 2020-08-03 criteria provided, single submitter clinical testing This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SMARCA4-related conditions. 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 C35"). 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. This sequence change replaces glutamic acid with aspartic acid at codon 365 of the SMARCA4 protein (p.Glu365Asp). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and aspartic acid.
Ambry Genetics RCV002456566 SCV002738397 uncertain significance Hereditary cancer-predisposing syndrome 2023-10-30 criteria provided, single submitter clinical testing The p.E365D variant (also known as c.1095G>C), located in coding exon 5 of the SMARCA4 gene, results from a G to C substitution at nucleotide position 1095. The glutamic acid at codon 365 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is highly 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). This variant has been detected in multiple individuals with no reported features of Coffin Siris syndrome (Ambry internal data). Based on the supporting evidence, the association of this alteration with rhabdoid tumor predisposition syndrome is unknown; however, the association of this alteration with Coffin-Siris syndrome is unlikely.
Breakthrough Genomics, Breakthrough Genomics RCV004692645 SCV005192576 uncertain significance not provided criteria provided, single submitter not provided

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