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

dbSNP: rs779769475

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000490024	SCV000551560	pathogenic	not provided	2023-12-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 53 of the SMARCB1 protein (p.Arg53Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with schwannomatosis (PMID: 18647326; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 410706). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on SMARCB1 function (PMID: 22949514, 26073604). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000490024	SCV000577245	pathogenic	not provided	2020-08-11	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: unable to rescue SMARCB1 null Drosophila specimens (Walker 2013); Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25772157, 26073604, 22949514, 18647326, 24933152, 31586052, 29907796)
Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine	RCV000785603	SCV000924182	uncertain significance	Schwannomatosis 1		criteria provided, single submitter	research
Ambry Genetics	RCV002402285	SCV002705714	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-04-17	criteria provided, single submitter	clinical testing	The p.R53L variant (also known as c.158G>T), located in coding exon 2 of the SMARCB1 gene, results from a G to T substitution at nucleotide position 158. The arginine at codon 53 is replaced by leucine, an amino acid with dissimilar properties. This alteration was detected in multiple unrelated families with schwannomatosis and segregated with disease in 4/4 affected relatives in one family (Boyd C et al. Clin Genet, 2008 Oct;74:358-66; Ambry internal data). Tumors analyzed from affected individuals has shown either loss of heterozygosity (wild type G allele) or deletion of the region encompassing SMARCB1 and NF2 along with third mutational events in NF2 (Piotrowski A et al. Nat Genet, 2014 Feb;46:182-7). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Missense and in-frame variants in SMARCB1 are known to cause neurodevelopmental disorders; however, such associations with rhabdoid tumor predisposition syndrome are exceedingly rare (Kosho T et al. Am J Med Genet C Semin Med Genet. 2014 Sep;166C(3):262-75; Eaton KW et al. Pediatr Blood Cancer. 2011 Jan;56(1):7-15). Based on the supporting evidence, this alteration is likely pathogenic for SMARCB1-related tumor predisposition syndrome; however, the association of this alteration with Coffin-Siris syndrome is unknown.