ClinVar Miner

Submissions for variant NM_003072.5(SMARCA4):c.1204A>G (p.Ile402Val)

gnomAD frequency: 0.00001  dbSNP: rs750861625
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV001010315 SCV001170492 uncertain significance Hereditary cancer-predisposing syndrome 2021-03-28 criteria provided, single submitter clinical testing The p.I402V variant (also known as c.1204A>G), located in coding exon 6 of the SMARCA4 gene, results from an A to G substitution at nucleotide position 1204. The isoleucine at codon 402 is replaced by valine, an amino acid with highly similar properties. This amino acid position is well 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.
Invitae RCV001037705 SCV001201133 uncertain significance Rhabdoid tumor predisposition syndrome 2 2023-06-05 criteria provided, single submitter clinical testing This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. 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. 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 not expected to disrupt SMARCA4 protein function. ClinVar contains an entry for this variant (Variation ID: 818587). This variant is present in population databases (rs750861625, gnomAD 0.003%). This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 402 of the SMARCA4 protein (p.Ile402Val).
Genome-Nilou Lab RCV001809898 SCV002056427 uncertain significance Intellectual disability, autosomal dominant 16 2021-07-15 criteria provided, single submitter clinical testing

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