ClinVar Miner

Submissions for variant NM_003072.5(SMARCA4):c.989C>T (p.Thr330Ile)

dbSNP: rs1555755082
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000569564 SCV000664137 uncertain significance Hereditary cancer-predisposing syndrome 2024-05-24 criteria provided, single submitter clinical testing The p.T330I variant (also known as c.989C>T), located in coding exon 5 of the SMARCA4 gene, results from a C to T substitution at nucleotide position 989. The threonine at codon 330 is replaced by isoleucine, 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000810630 SCV000950851 uncertain significance Rhabdoid tumor predisposition syndrome 2 2023-07-18 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 330 of the SMARCA4 protein (p.Thr330Ile). 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: 480586). This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. This variant is not present in population databases (gnomAD no frequency).
Genome-Nilou Lab RCV001809571 SCV002056398 uncertain significance Intellectual disability, autosomal dominant 16 2021-07-15 criteria provided, single submitter clinical testing
Baylor Genetics RCV001809571 SCV003835844 uncertain significance Intellectual disability, autosomal dominant 16 2022-11-11 criteria provided, single submitter clinical testing
Baylor Genetics RCV000810630 SCV005052769 uncertain significance Rhabdoid tumor predisposition syndrome 2 2023-12-27 criteria provided, single submitter clinical testing

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