Submissions for variant NM_003073.5(SMARCB1):c.110G>A (p.Arg37His)

dbSNP: rs398122368

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000262341	SCV000329523	pathogenic	not provided	2019-08-20	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 29907796, 22726846, 25168959)
SIB Swiss Institute of Bioinformatics	RCV000074462	SCV000883290	uncertain significance	Intellectual disability, autosomal dominant 15	2018-10-15	criteria provided, single submitter	curation	This variant is interpreted as Uncertain Significance - Insufficient Evidence, for Coffin-Siris syndrome 3, autosomal dominant. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PM6 => Assumed de novo, but without confirmation of paternity and maternity (https://www.ncbi.nlm.nih.gov/pubmed/22726846).
Baylor Genetics	RCV001533133	SCV001748953	pathogenic	SMARCB1-related BAFopathy	2021-06-10	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000074462	SCV002023594	likely pathogenic	Intellectual disability, autosomal dominant 15	2021-07-15	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, University of Torino	RCV000074462	SCV004171091	likely pathogenic	Intellectual disability, autosomal dominant 15		criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV004556052	SCV005045226	likely pathogenic	Coffin-Siris syndrome	2024-05-16	criteria provided, single submitter	curation	The heterozygous p.Arg37His variant in SMARCB1 was identified by our study in one individual with Coffin-Siris syndrome. The p.Arg37His variant in SMARCB1 has been reported in >10 individuals with Coffin-Siris syndrome (PMIDs: 22726846, 29907796, 33057194, 34906496, 36964972), but was absent from large population studies. The number of reported affected individuals with this variant is greater than expected compared to non-affected individuals with this variant. This variant has been reported in ClinVar (Variation ID: 88893) and has been interpreted as uncertain significance by two submitters, likely pathogenic by two submitters, and pathogenic by three submitters. This variant is assumed de novo in 11 individuals, but maternity and paternity have not been confirmed (PMIDs: 22726846, 29907796, 34906496, 36964972). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The number of missense variants reported in SMARCB1 in the general population is lower than expected, suggesting there is little benign variation in this gene and slightly increasing the possibility that a missense variant in this gene may not be tolerated. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal dominant Coffin-Siris syndrome. ACMG/AMP Criteria applied: PM2_Supporting, PS4_Moderate, PP2, PM6, PP3_Moderate (Richards 2015).
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000262341	SCV005198297	likely pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000074462	SCV005398311	pathogenic	Intellectual disability, autosomal dominant 15	2024-10-09	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative, loss of function and gain of function are all known mechanisms of disease in this gene. Loss of function variants are associated with cancer susceptibility (rhabdoid tumor predisposition syndrome 1 (MIM#609322), schwannomatosis-1 (MIM#162091), rhabdoid tumors somatic (MIM#609322)). An inframe deletion variant, missense variants and truncating variants escaping nonsense-mediated decay have all been reported to have either a gain of function or dominant negative mechanism, and are associated with Coffin-Siris syndrome 3 (MIM#614608) (OMIM, PMID: 31759698). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and high conservation. (I) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in gnomAD). This variant is located in the DNA binding domain (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been observed de novo in multiple affected individuals (PMIDs: 29907796, 34906496, 31172278). In addition, it has been reported as pathogenic and likely pathogenic by multiple clinical laboratories (ClinVar). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Daryl Scott Lab, Baylor College of Medicine	RCV000074462	SCV005871365	pathogenic	Intellectual disability, autosomal dominant 15	2024-01-01	criteria provided, single submitter	clinical testing	PS2, PM2, PM5, PP3
OMIM	RCV000074462	SCV000108478	pathogenic	Intellectual disability, autosomal dominant 15	2012-07-13	no assertion criteria provided	literature only
Baylor Genetics	RCV000074462	SCV000807306	uncertain significance	Intellectual disability, autosomal dominant 15	2017-09-01	flagged submission	clinical testing	This variant has been previously reported as disease-causing and was found twice in our laboratory de novo: in a 6-year-old male with global delays, autism spectrum, hypotonia, hydrocephalus, VUR, agenesis of the corpus callosum, myopia, pes cavus, elevated free T4; in an 8-year-old female with intellectual disability, behavior problems, hydrocephalus, dysmorphisms, amblyopia, myopic astigmatixm, hypoplastic labia majora, hypertonia, decreased muscle mass, dysphagia, Wilms tumor