Submissions for variant NM_024009.3(GJB3):c.293G>A (p.Arg98His)

gnomAD frequency: 0.00006  dbSNP: rs201314683

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000156165	SCV000205881	uncertain significance	not specified	2015-01-06	criteria provided, single submitter	clinical testing	The p.Arg98His variant in GJB3 has been previously identified by our laboratory in 1 Hispanic individual with hearing loss. This variant has also been identifie d in 8/67672 of European chromosomes and 1/11600 Latino chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs201314683 ). Computational prediction tools and conservation analysis do not provide stron g support for or against an impact to the protein. In summary, the clinical sign ificance of the p.Arg98His variant is uncertain.
Illumina Laboratory Services, Illumina	RCV001101939	SCV001258582	likely benign	Erythrokeratodermia variabilis et progressiva 1	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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
GeneDx	RCV002466451	SCV002762201	uncertain significance	not provided	2022-06-06	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV002516152	SCV003704974	uncertain significance	Inborn genetic diseases	2022-03-03	criteria provided, single submitter	clinical testing	The c.293G>A (p.R98H) alteration is located in exon 2 (coding exon 1) of the GJB3 gene. This alteration results from a G to A substitution at nucleotide position 293, causing the arginine (R) at amino acid position 98 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002466451	SCV004523713	uncertain significance	not provided	2023-11-02	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 98 of the GJB3 protein (p.Arg98His). This variant is present in population databases (rs201314683, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal dominant erythrokeratodermia variabilis (PMID: 35677558). ClinVar contains an entry for this variant (Variation ID: 179376). 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 not expected to disrupt GJB3 protein function with a negative predictive value of 80%. 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.