ClinVar Miner

Submissions for variant NM_003072.5(SMARCA4):c.3205A>G (p.Ile1069Val)

dbSNP: rs1555781098
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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 RCV000547453 SCV000648047 uncertain significance Rhabdoid tumor predisposition syndrome 2 2017-06-25 criteria provided, single submitter clinical testing This variant is not present in population databases (ExAC no frequency). 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with SMARCA4-related disease. This sequence change replaces isoleucine with valine at codon 1069 of the SMARCA4 protein (p.Ile1069Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine.
Ambry Genetics RCV004024136 SCV005038358 uncertain significance Hereditary cancer-predisposing syndrome 2024-01-11 criteria provided, single submitter clinical testing The p.I1069V variant (also known as c.3205A>G), located in coding exon 22 of the SMARCA4 gene, results from an A to G substitution at nucleotide position 3205. The isoleucine at codon 1069 is replaced by valine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species, and valine is the reference amino acid in other 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.

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