ClinVar Miner

Submissions for variant NM_003072.5(SMARCA4):c.1028T>C (p.Val343Ala)

dbSNP: rs1568427296
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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 RCV000689263 SCV000816905 uncertain significance Rhabdoid tumor predisposition syndrome 2 2023-12-01 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 343 of the SMARCA4 protein (p.Val343Ala). This variant is not present in population databases (gnomAD no frequency). 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: 568800). 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.
Ambry Genetics RCV003163131 SCV003901226 uncertain significance Hereditary cancer-predisposing syndrome 2022-11-01 criteria provided, single submitter clinical testing The p.V343A variant (also known as c.1028T>C), located in coding exon 5 of the SMARCA4 gene, results from a T to C substitution at nucleotide position 1028. The valine at codon 343 is replaced by alanine, an amino acid with similar properties. This amino acid position is highly 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.
PreventionGenetics, part of Exact Sciences RCV003420223 SCV004107213 uncertain significance SMARCA4-related disorder 2023-02-08 criteria provided, single submitter clinical testing The SMARCA4 c.1028T>C variant is predicted to result in the amino acid substitution p.Val343Ala. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. It is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/568800/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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