Submissions for variant NM_018723.4(RBFOX1):c.353G>A (p.Arg118Gln)

dbSNP: rs1057521725

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000443683	SCV000524237	uncertain significance	not provided	2023-06-08	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015)
Revvity Omics, Revvity	RCV000443683	SCV004236557	uncertain significance	not provided	2020-10-27	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003638654	SCV004387234	uncertain significance	Idiopathic generalized epilepsy	2023-07-13	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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 RBFOX1 protein function. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 138 of the RBFOX1 protein (p.Arg138Gln). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RBFOX1-related conditions. ClinVar contains an entry for this variant (Variation ID: 383748).
Ambry Genetics	RCV004022378	SCV004937976	pathogenic	Inborn genetic diseases	2024-01-10	criteria provided, single submitter	clinical testing	The c.413G>A (p.R138Q) alteration is located in exon 3 (coding exon 3) of the RBFOX1 gene. This alteration results from a G to A substitution at nucleotide position 413, causing the arginine (R) at amino acid position 138 to be replaced by a glutamine (Q). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant (also known as c.353G>A p.R118Q) has been determined to be the result of a de novo mutation in multiple individuals with features consistent with RBFOX1-related neurodevelopmental disorder (Li, 2024). This amino acid position is highly conserved in available vertebrate species. Functional analysis utilizing an in vitro minigene system has shown that p.R138Q (also known as p.R118Q) impairs splicing function (Li, 2024). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.