Submissions for variant NM_003070.5(SMARCA2):c.3314G>C (p.Arg1105Pro)

dbSNP: rs281875197

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV002255112	SCV002526442	likely pathogenic	Nicolaides-Baraitser syndrome	2022-06-20	criteria provided, single submitter	clinical testing
GeneDx	RCV000059671	SCV004170082	likely pathogenic	not provided	2023-10-31	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 22366787, 35811451, 24090879)
Invitae	RCV000059671	SCV004295974	likely pathogenic	not provided	2023-07-17	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 68770). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg1105 amino acid residue in SMARCA2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22366787). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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) performed at Invitae indicates that this missense variant is expected to disrupt SMARCA2 protein function. This missense change has been observed in individuals with Nicolaides-Baraitser syndrome (PMID: 22366787; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 1105 of the SMARCA2 protein (p.Arg1105Pro).
UniProtKB/Swiss-Prot	RCV000059671	SCV000091241	not provided	not provided		no assertion provided	not provided
Child and Adolescent Psychiatry Residency Program, Foundation for Education and Research in Health Sciences	RCV002255112	SCV003930365	pathogenic	Nicolaides-Baraitser syndrome		no assertion criteria provided	clinical testing	PS4: The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls PM1: Located in a mutational hot spot and/or critical and well-established functional domain PM2: Absent from controls (or at extremely low frequency if recessive) from ExAC, 1000Genomas, A3raM, TOPMED, and population databases. PM5: Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before (p.R1105H, p.R1105C) (Sousa, Hennekam; Nicolaides-Baraitser Syndrome International Consortium, 2014). PM6: variant described as de novo, without confirmatory maternity and paternity analysis. PP3: Multiple lines of computational evidence support a deleterious effect on the gene or gene product [CADD = 34.0].