ClinVar Miner

Submissions for variant NM_003073.5(SMARCB1):c.158G>T (p.Arg53Leu) (rs779769475)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000490024 SCV000551560 uncertain significance not provided 2020-05-11 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 53 of the SMARCB1 protein (p.Arg53Leu). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with schwannomatosis in five individuals in two unrelated families. All analyzed tumors displayed loss of heterozygosity of the wild-type allele (PMID: 18647326). An experimental study has reported that this variant does not impact the capability of SMARCB1 to suppress cyclin D1 activity in cultured cells (PMID: 22949514). However, structural analysis of the SMARCB1 protein showed that this residue is located on the surface of the protein-DNA interaction. Unsuccessful attempts to express SMARCB1 carrying this variant suggested that the loss of this interaction destabilizes the fold of the domain (PMID: 26073604). The clinical significance of these findings is uncertain. In summary, this variant is a rare missense change that is absent in the population and segregates with disease in two families. However, whether or not this variant disrupts SMARCB1 function remains unknown. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000490024 SCV000577245 pathogenic not provided 2018-11-19 criteria provided, single submitter clinical testing The R53L variant has been reported previously in blood and tumor samples from two unrelated individuals who met criteria for 'definitive' or 'presumptive' schwannomatosis and was found to segregate in other affected family members (Boyd et al., 2008). In one of the families, a somatic variant in NF2 was also identified in the tumor specimen (Boyd et al., 2008). The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R53L 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 within a DNA binding domain where amino acids with similar properties to Arginine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Functional studies have shown R53L fails to rescue SMARCB1 null Drosophila specimens (Walker et al., 2013). In summary, we consider this variant to be pathogenic.
Baylor-Hopkins Center for Mendelian Genomics,Johns Hopkins University RCV000785603 SCV000924182 uncertain significance Schwannomatosis 1 criteria provided, single submitter research

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