ClinVar Miner

Submissions for variant NM_003072.5(SMARCA4):c.908T>C (p.Ile303Thr)

gnomAD frequency: 0.00001  dbSNP: rs778446601
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001340445 SCV001534254 uncertain significance Rhabdoid tumor predisposition syndrome 2 2022-12-06 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 1037314). 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. This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. This variant is present in population databases (rs778446601, gnomAD 0.007%). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 303 of the SMARCA4 protein (p.Ile303Thr).
Ambry Genetics RCV002447394 SCV002683090 uncertain significance Hereditary cancer-predisposing syndrome 2023-08-29 criteria provided, single submitter clinical testing The p.I303T variant (also known as c.908T>C), located in coding exon 5 of the SMARCA4 gene, results from a T to C substitution at nucleotide position 908. The isoleucine at codon 303 is replaced by threonine, an amino acid with similar properties. 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.

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