Submissions for variant NM_004004.6(GJB2):c.94C>T (p.Arg32Cys)

gnomAD frequency: 0.00017  dbSNP: rs371024165

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000724651	SCV000331831	pathogenic	not provided	2018-02-09	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000614720	SCV000710857	pathogenic	Rare genetic deafness	2017-10-26	criteria provided, single submitter	clinical testing	The p.Arg32Cys variant in GJB2 has been reported in at least 13 individuals with hearing loss, including 3 homozygotes and 8 compound heterozygotes, and segrega ted with hearing loss in two additional family members in two families (Prasad 2 000, Cryns 2004, Primignani 2009, Dai 2009, Shan 2010, Dodson 2011, Bazazzadegan 2012, Xia 2016, Moctar 2016, LMM data). This variant has also been reported in ClinVar (Variation ID# 188758) as likely pathogenic. It has been identified in 10/24020 African chromosomes by the Genome Aggregation Database (gnomAD, http:// gnomad.broadinstitute.org; dbSNP rs371024165); however, its frequency is low eno ugh to be consistent with the carrier frequency for recessive hearing loss. In s ummary, the p.Arg32Cys variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss based on the previously reported homozygous an d compound heterozygous affected individuals and statistically significant incre ase of allele frequency in affected individuals over the general population. ACM G/AMP Criteria applied: PM3_S; PS4 (Richards 2015).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169075	SCV000917436	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2017-09-01	criteria provided, single submitter	clinical testing	Variant summary: The GJB2 c.94C>T (p.Arg32Cys) variant causes a missense change involving the alteration of a conserved nucleotide located in the Connexin, N-terminal domain (IPR013092) (InterPro). 5/5 in silico tools predict damaging outcome for this variant. The variant was found in the control population dataset of ExAC and publications in 5/122742 control chromosomes at a frequency of 0.0000407, which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.025). This variant was reported in several patients with NSHL in homozygous state and compound heterozygous state with other pathogenic variants, including evidence of cosegregation with disease (Prasad_2000, Pandya_2003, Toth_2004, Snoeckx_2005, Dai_2009, Shan_2010, Dodson_2011, Bazazzadegan_2012, Rayess_2015). Multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic. Another missense change at the same residue p.Arg32His has also been classified as pathogenic by multiple submitters in ClinVar. Taken together, this variant is classified as pathogenic.
Athena Diagnostics Inc	RCV000724651	SCV001143676	pathogenic	not provided	2020-10-21	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant appears to segregate with disease in at least one family, however, the available information does not rule out segregation due to chance. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Computational tools predict that this variant is damaging.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001001448	SCV001158689	pathogenic	not specified	2018-09-28	criteria provided, single submitter	clinical testing	The GJB2 (Connexin 26) c.94C>T; p.Arg32Cys variant (rs371024165) has been previously identified in patients with a suspicion of GJB2-realted deafness, either as a homozygote (Moctar 2016), or as part of a trans-heterozygous (bi-allelic) combination with another pathogenic variant (Prasad 2000, Xia 2016, Moctar 2016). It has also been identified as a rare variant in several large-scale sequencing studies of affected populations (selected references: Snoeckx 2005, Dodson 2011, de la Luz Arenas-Sordo 2012, Bazazzadegan 2012). Consistent with a recessive carrier frequency, this variant is found in the general population with an allele frequency in African populations of 0.04% (10/24,020 alleles) in the Genome Aggregation Database. The arginine residue at this position is highly conserved across multiple species (Alamut Software v 2.11), and computational programs (SIFT, PolyPhen2) predict this variant to be damaging to protein function. Additionally, as listed in the HGMD database (Stenson 2017) other amino acid substitutions at this codon have been implicated in hearing loss (Gly, His, Leu, Ser). Taken together, we consider the c.94C>T; p.Arg32Cys variant to be pathogenic.
Invitae	RCV000724651	SCV001391719	pathogenic	not provided	2023-12-21	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 32 of the GJB2 protein (p.Arg32Cys). This variant is present in population databases (rs371024165, gnomAD 0.04%). This missense change has been observed in individual(s) with autosomal recessive non-syndromic deafness (PMID: 11102979, 19371219, 21465647, 26346709, 27045574). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 188758). 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 GJB2 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg32 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19157576, 20154630, 22925408). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000724651	SCV001827024	pathogenic	not provided	2021-11-09	criteria provided, single submitter	clinical testing	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: 27153395, 27045574, 19366456, 25087612, 25388846, 12865758, 16380907, 25270357, 14985372, 20381175, 27067584, 26540915, 22925408, 20083784, 19235794, 19157576, 17666888, 15967879, 12885339, 21465647, 31163360, 22695344, 15146474, 26346709, 19390476, 15365987, 11102979, 19371219, 30275481)
MGZ Medical Genetics Center	RCV000169075	SCV002579589	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2021-11-18	criteria provided, single submitter	clinical testing
Counsyl	RCV000169075	SCV000220243	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2016-09-09	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000169075	SCV001453359	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2020-09-16	no assertion criteria provided	clinical testing