Submissions for variant NM_004004.6(GJB2):c.506G>A (p.Cys169Tyr)

gnomAD frequency: 0.00001  dbSNP: rs774518779

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000256090	SCV000322423	pathogenic	not provided	2022-06-17	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect as the p.(C169Y) variant results in disruption of junction channel formation, and disrupts the disulfide bridge that typically forms between the C169 and C64 residues (Zonta et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); 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: 24551843, 25388846, 15365987, 34354426, 22103400, 25628337)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587164	SCV000698263	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2017-06-20	criteria provided, single submitter	clinical testing	Variant summary: The GJB2 c.506G>A (p.Cys169Tyr) variant involves the alteration of a conserved nucleotide. "Cys169 is one of the six extracellular cysteine residues which are conserved in all connexin isoforms. These six cysteines form three disulfide bridges, which are likely to play an important role in guiding the correct folding of the connexin protein and the docking of the two hexameric hemichannels in the extracellular region" via Zonta_2015. 4/4 in silico tools predict a damaging outcome. A functional study, Zonta_2015 supports these predictions and showed that the variant "At the cellular level, our results show that the mutant protein fails to form junctional channels in HeLa transfectants despite being correctly targeted to the plasma membrane. At the molecular level, this effect can be accounted for by disruption of the disulfide bridge that Cys169 forms with Cys64 in the wild-type structure (Cx26WT)." This variant was found in 2/121012 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.025). Multiple publications have cited the variant in homozygous affected individuals, in addition a heterozygous affected individual, which a second mutation was not indicated to have been found. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000763322	SCV000893999	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A; Mutilating keratoderma; Ichthyosis, hystrix-like, with hearing loss; Autosomal dominant keratitis-ichthyosis-hearing loss syndrome; Palmoplantar keratoderma-deafness syndrome; Knuckle pads, deafness AND leukonychia syndrome; Autosomal dominant nonsyndromic hearing loss 3A; X-linked mixed hearing loss with perilymphatic gusher	2018-10-31	criteria provided, single submitter	clinical testing
Genetic Diagnostics Department, Viafet Genomics Laboratory	RCV000587164	SCV001976447	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2021-08-23	criteria provided, single submitter	clinical testing	As part of Carrier Screening testing performed at Viafet Genomics Laboratory, this variant was identified in a heterozygous state in 2 family members who are not affected with this condition. This variant has been identified in a homozygous state in several patients affected with hearing loss (PMIDs: 24551843 and 25628337). In addition, functional studies have revealed that this variant fails to form junctional channels in vitro despite being correctly targeted to the plasma membrane (PMID: 25628337).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017573	SCV004847924	pathogenic	Rare genetic deafness	2022-06-23	criteria provided, single submitter	clinical testing	The p.Cys169Tyr variant in GJB2 has been reported in three homozygous and two heterozygous individuals with hearing loss and segregated with disease in seven affected individuals from three families (Zonta 2015 PMID: 25628337, Birkenhäger 2014 PMID: 24551843, Azaiez 2004 PMID: 15365987, Mahfood 2021 PMID: 34354426). It has also been identified in 0.00176% (2/113464) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and reported in ClinVar (Variation ID 265481). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. This variant disrupts one of six conserved cysteine residues that form intramolecular disulfide bonds and are critical for intercellular channel formation (Zonta 2015 PMID: 25628337, Birkenhäger 2014 PMID: 24551843, Dahl 1991 PMID: 1707811). In vitro functional studies provide some evidence that this variant impacts protein function by obliterating the formation of gap junction plaques at points of cell-to-cell contact (Zonta 2015 PMID: 25628337); however, these types of assays may not accurately represent biological function. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss. ACMG/AMP Criteria applied: PP1_Strong; PM1; PM3; PM2_Supporting; PP3; PS3_Supporting.
Natera, Inc.	RCV000587164	SCV001463363	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2020-09-16	no assertion criteria provided	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000587164	SCV004806831	uncertain significance	Autosomal recessive nonsyndromic hearing loss 1A	2024-03-26	flagged submission	clinical testing