Submissions for variant NM_024009.3(GJB3):c.223C>T (p.Arg75Cys)

gnomAD frequency: 0.00034  dbSNP: rs370476720

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000359108	SCV000357293	likely benign	Erythrokeratodermia variabilis et progressiva 1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
GeneDx	RCV000498188	SCV000590068	uncertain significance	not provided	2023-08-23	criteria provided, single submitter	clinical testing	Maternally inherited variant in a patient with congenital anomalies of the kidney and urinary tract reported in the published literature (Bekheirnia et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 35640668, 35368817)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000498188	SCV003247754	uncertain significance	not provided	2022-11-10	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 GJB3 protein function. ClinVar contains an entry for this variant (Variation ID: 297191). This variant has not been reported in the literature in individuals affected with GJB3-related conditions. This variant is present in population databases (rs370476720, gnomAD 0.02%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 75 of the GJB3 protein (p.Arg75Cys).
Ambry Genetics	RCV004021442	SCV004876990	uncertain significance	Inborn genetic diseases	2021-08-30	criteria provided, single submitter	clinical testing	The c.223C>T (p.R75C) alteration is located in exon 2 (coding exon 1) of the GJB3 gene. This alteration results from a C to T substitution at nucleotide position 223, causing the arginine (R) at amino acid position 75 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000498188	SCV001551274	uncertain significance	not provided		no assertion criteria provided	clinical testing	The GJB3 p.Arg75Cys variant was not identified in the literature. The variant was identified in dbSNP (ID: rs370476720) and ClinVar (classified as uncertain significance by GeneDx and as likely benign by Illumina). The variant was identified in control databases in 42 of 282762 chromosomes at a frequency of 0.0001485 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 34 of 129116 chromosomes (freq: 0.000263), Other in 1 of 7222 chromosomes (freq: 0.000139), African in 3 of 24950 chromosomes (freq: 0.00012), Latino in 3 of 35430 chromosomes (freq: 0.000085) and South Asian in 1 of 30616 chromosomes (freq: 0.000033), but was not observed in the Ashkenazi Jewish, East Asian, or European (Finnish) populations. The p.Arg75 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003949993	SCV004772889	uncertain significance	GJB3-related disorder	2023-12-07	no assertion criteria provided	clinical testing	The GJB3 c.223C>T variant is predicted to result in the amino acid substitution p.Arg75Cys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.026% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.