ClinVar Miner

Submissions for variant NM_003072.5(SMARCA4):c.4171-1821C>G

dbSNP: rs1600445482
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV001022024 SCV001183712 uncertain significance Hereditary cancer-predisposing syndrome 2023-07-17 criteria provided, single submitter clinical testing The p.T1400R variant (also known as c.4199C>G), located in coding exon 29 of the SMARCA4 gene, results from a C to G substitution at nucleotide position 4199. The threonine at codon 1400 is replaced by arginine, an amino acid with similar properties. This alteration was detected in a patient with Small cell carcinoma of hypercalcemic type (SCCOHT), however, this patient was positive for a second alteration in SMARCA4 that was classified as likely pathogenic by the authors (Sirák I et al. Pathol Oncol Res, 2021 Dec;27:1610003). This amino acid position is conserved on limited sequence alignment. 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 RCV001052895 SCV001217130 uncertain significance Rhabdoid tumor predisposition syndrome 2 2022-04-27 criteria provided, single submitter clinical testing This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 1400 of the SMARCA4 protein (p.Thr1400Arg). This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. ClinVar contains an entry for this variant (Variation ID: 824662). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.

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