Submissions for variant NM_003072.5(SMARCA4):c.442G>A (p.Gly148Arg)

gnomAD frequency: 0.00026  dbSNP: rs138689221

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000204451	SCV000261340	likely benign	Rhabdoid tumor predisposition syndrome 2	2024-01-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000267497	SCV000410454	benign	Coffin-Siris syndrome	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Ambry Genetics	RCV000563484	SCV000663901	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-23	criteria provided, single submitter	clinical testing	The p.G148R variant (also known as c.442G>A), located in coding exon 3 of the SMARCA4 gene, results from a G to A substitution at nucleotide position 442. The glycine at codon 148 is replaced by arginine, an amino acid with dissimilar properties. 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 has been detected in multiple individuals with no reported features of Coffin-Siris syndrome-associated disease (Ambry internal data). This alteration was detected in an individual with ovarian cancer; however, limited clinical information was provided (Kanchi KL et al. Nat Commun, 2014;5:3156). 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 rhabdoid tumor predisposition syndrome is unknown; however, the association of this alteration with Coffin-Siris syndrome is unlikely.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000204451	SCV000891051	likely benign	Rhabdoid tumor predisposition syndrome 2	2021-01-06	criteria provided, single submitter	clinical testing	The SMARCA4 c.442G>A (p.Gly148Arg) missense change has a maximum subpopulation frequency of 0.077% in gnomAD v3.1 (https://gnomad.broadinstitute.org/variant/19-10986275-G-A). This population frequency is higher than expected for a pathogenic variant in SMARCA4 causing Rhabdoid Tumor Predisposition Syndrome (BS1). In silico tools predict a deleterious effect on the gene or protein function (PP3), however to our knowledge these predictions have not been confirmed by functional studies. This variant has been identified in one individual without a personal or family history of rhabdoid tumors or Coffin-Siris syndrome (internal data). It has also been observed in a case of atypical teratoid/rhabdoid tumor with an alternative molecular basis for disease (BP5; internal data). In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria: BS1, BP5, PP3.
GeneDx	RCV001651067	SCV001871126	uncertain significance	not provided	2022-09-30	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Genome-Nilou Lab	RCV001808563	SCV002057906	likely benign	Intellectual disability, autosomal dominant 16	2021-07-15	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001808563	SCV003823971	uncertain significance	Intellectual disability, autosomal dominant 16	2020-06-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001651067	SCV004220453	likely benign	not provided	2023-05-26	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003947674	SCV004761058	likely benign	SMARCA4-related disorder	2022-10-06	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).