ClinVar Miner

Submissions for variant NM_003072.5(SMARCA4):c.1108C>T (p.Arg370Cys)

dbSNP: rs1436490540
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000567994 SCV000664254 uncertain significance Hereditary cancer-predisposing syndrome 2021-05-11 criteria provided, single submitter clinical testing The p.R370C variant (also known as c.1108C>T), located in coding exon 5 of the SMARCA4 gene, results from a C to T substitution at nucleotide position 1108. The arginine at codon 370 is replaced by cysteine, an amino acid with highly dissimilar properties. 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). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics RCV000765418 SCV000896702 uncertain significance Rhabdoid tumor predisposition syndrome 2; Intellectual disability, autosomal dominant 16 2018-10-31 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001234913 SCV001407574 uncertain significance Rhabdoid tumor predisposition syndrome 2 2023-05-18 criteria provided, single submitter clinical testing 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SMARCA4 protein function. ClinVar contains an entry for this variant (Variation ID: 480659). 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). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 370 of the SMARCA4 protein (p.Arg370Cys).
Genome-Nilou Lab RCV001809599 SCV002056415 uncertain significance Intellectual disability, autosomal dominant 16 2021-07-15 criteria provided, single submitter clinical testing

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