Submissions for variant NM_003072.5(SMARCA4):c.4902A>C (p.Glu1634Asp)

dbSNP: rs2147127066

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001373964	SCV001570712	uncertain significance	Rhabdoid tumor predisposition syndrome 2	2022-12-25	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) 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: 1064050). 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 glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 1666 of the SMARCA4 protein (p.Glu1666Asp).
GeneDx	RCV001751737	SCV001988133	uncertain significance	not provided	2018-12-06	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Genome-Nilou Lab	RCV001810040	SCV002057011	uncertain significance	Intellectual disability, autosomal dominant 16	2021-07-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002341813	SCV002642311	uncertain significance	Hereditary cancer-predisposing syndrome	2024-07-23	criteria provided, single submitter	clinical testing	The p.E1666D variant (also known as c.4998A>C), located in coding exon 34 of the SMARCA4 gene, results from an A to C substitution at nucleotide position 4998. The glutamic acid at codon 1666 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is well 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.