Submissions for variant NM_003072.5(SMARCA4):c.4558C>T (p.Arg1520Cys)

dbSNP: rs1057523119

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000437315	SCV000530783	uncertain significance	not provided	2016-08-11	criteria provided, single submitter	clinical testing	The R1552C variant in the SMARCA4 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R1552C variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R1552C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and is located within the bromo domain. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R1552C as a variant of uncertain significance,
Labcorp Genetics (formerly Invitae), Labcorp	RCV000692029	SCV000819836	uncertain significance	Rhabdoid tumor predisposition syndrome 2	2024-02-14	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1552 of the SMARCA4 protein (p.Arg1552Cys). 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: 388472). 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. 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	RCV001808820	SCV002056959	uncertain significance	Intellectual disability, autosomal dominant 16	2021-07-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004668970	SCV005167003	uncertain significance	Hereditary cancer-predisposing syndrome	2024-05-28	criteria provided, single submitter	clinical testing	The p.R1552C variant (also known as c.4654C>T), located in coding exon 32 of the SMARCA4 gene, results from a C to T substitution at nucleotide position 4654. The arginine at codon 1552 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.