ClinVar Miner

Submissions for variant NM_003072.5(SMARCA4):c.1836G>A (p.Met612Ile)

dbSNP: rs1600132619
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV001013332 SCV001173908 uncertain significance Hereditary cancer-predisposing syndrome 2021-11-24 criteria provided, single submitter clinical testing The p.M612I variant (also known as c.1836G>A), located in coding exon 11 of the SMARCA4 gene, results from a G to A substitution at nucleotide position 1836. The methionine at codon 612 is replaced by isoleucine, an amino acid with highly 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.
Invitae RCV001208234 SCV001379611 uncertain significance Rhabdoid tumor predisposition syndrome 2 2019-06-16 criteria provided, single submitter clinical testing This sequence change replaces methionine with isoleucine at codon 612 of the SMARCA4 protein (p.Met612Ile). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SMARCA4-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Genome-Nilou Lab RCV001809906 SCV002056460 uncertain significance Intellectual disability, autosomal dominant 16 2021-07-15 criteria provided, single submitter clinical testing

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