ClinVar Miner

Submissions for variant NM_003072.5(SMARCA4):c.1765G>A (p.Ala589Thr)

gnomAD frequency: 0.00001  dbSNP: rs765850087
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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 RCV000687814 SCV000815402 uncertain significance Rhabdoid tumor predisposition syndrome 2 2024-06-08 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 589 of the SMARCA4 protein (p.Ala589Thr). This variant is present in population databases (rs765850087, gnomAD 0.0009%). 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: 567661). 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 with a negative predictive value of 95%. 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.
Sema4, Sema4 RCV002257928 SCV002532792 uncertain significance Hereditary cancer-predisposing syndrome 2021-12-28 criteria provided, single submitter curation
Ambry Genetics RCV002257928 SCV002713358 uncertain significance Hereditary cancer-predisposing syndrome 2023-09-19 criteria provided, single submitter clinical testing The p.A589T variant (also known as c.1765G>A), located in coding exon 10 of the SMARCA4 gene, results from a G to A substitution at nucleotide position 1765. The alanine at codon 589 is replaced by threonine, an amino acid with 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.

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