Submissions for variant NM_004004.6(GJB2):c.35del (p.Gly12fs) (rs80338939)

Total submissions: 34

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel,	RCV000211775	SCV000840537	pathogenic	Nonsyndromic hearing loss and deafness	2018-09-20	reviewed by expert panel	curation	The c.35delG variant in GJB2 is predicted to cause a premature stop codon in biologically-relevant-exon 2/2 that leads to a truncated or absent protein in a gene in which loss-of-function is an established mechanism (PVS1). This variant has been detected in patients with hearing loss in trans with at least 4 pathogenic or suspected-pathogenic variants (PM3_VS; PMID: 26445815). This variant was found to have a statistically higher prevalence in affected individuals over controls (PS4; PMID: 26969326, 25999548). The filtering allele frequency of the c.35delG variant in the GJB2 gene is 0.9% for European (Non-Finnish) chromosomes in the Genome Aggregation Database (1207/124552 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). The ClinGen Hearing Loss Expert Panel believes that the evidence for the pathogenicity of this variant for hearing loss outweighs the high allele frequency of the variant in population databases. Therefore, the BA1 code will not contribute to the overall classification. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive non-syndromic hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PVS1, PM3_VS, PS4, BA1.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine	RCV000844702	SCV000061505	pathogenic	Rare genetic deafness	2018-03-01	criteria provided, single submitter	clinical testing	The c.35delG variant in GJB2 is known to be pathogenic with many supporting publ ications. ACMG/AMP Criteria applied: PVS1, PM3_VeryStrong.
Genetic Services Laboratory, University of Chicago	RCV000146019	SCV000193171	pathogenic	Hearing impairment	2013-02-08	criteria provided, single submitter	clinical testing
Knight Diagnostic Laboratories,Oregon Health and Sciences University	RCV000018527	SCV000223930	pathogenic	Deafness, autosomal recessive 1A	2016-03-14	criteria provided, single submitter	clinical testing	The c.35delG (p.Gly12Valfs*2) frameshift variant introduces a premature stop codon, leading to the truncation of the Connexin 26 protein. The c.35delG variant represents the most common pathogenic variant in Caucasian patients with genetic sensorineural deafness (Carrasquillo et al. 1997; Denoyelle et al. 1997; Zelante et al. 1997; Green et al. 1999; Gasparini et al. 2000; Kenneson et al. 2002; Bouwer et al. 2007). Therefore, this collective evidence supports the classification of the c.35delG (p.Gly12Valfs*2) as a Pathogenic variant for Nonsyndromic hearing loss.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics	RCV000080373	SCV000227317	pathogenic	not provided	2016-01-04	criteria provided, single submitter	clinical testing	The c.35delG deletion is the most common pathogenic variant associated with hearing loss. Www.ncbi.nlm.nih.gov/books/NBK1272/1
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia	RCV000080373	SCV000257945	pathogenic	not provided	2015-11-16	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics	RCV000080373	SCV000280697	pathogenic	not provided	2014-11-24	criteria provided, single submitter	clinical testing
GeneDx	RCV000080373	SCV000321725	pathogenic	not provided	2018-10-26	criteria provided, single submitter	clinical testing	The c.35delG variant in the GJB2 gene has been reported previously in association with autosomal recessive nonsyndromic hearing loss when present in the homozygous state or when in trans with another pathogenic variant (Kenneson et al., 2002). The c.35delG variant is the most common GJB2 pathogenic variant among individuals of European background (Gasparini et al., 2000), and the hearing loss present in individuals homozygous for the c.35delG variant ranges from mild to profound (Hilgert et al., 2009). Most individuals known to be heterozygous for the c.35delG variant have normal hearing, although subclinical differences in the otoacoustic emissions of carriers has been noted upon audiologic examination (Morell et al., 1998). The c.35delG variant causes a frameshift starting with codon Glycine 12, changes this amino acid to a Valine residue, and creates a premature Stop codon at position 2 of the new reading frame, denoted p.Gly12ValfsX2. This variant is predicted to cause loss of normal protein function through protein truncation. The c.35delG variant is observed in 1,207/124,552 alleles (0.97%) from individuals of non-Finnish European background in large population cohorts, including 10 homozygous individuals (Lek et al., 2016). In vitro studies demonstrate that the c.35delG variant results in a loss of connexin 26 function (D'Andrea et al., 2002). We interpret c.35delG as a pathogenic variant.
Counsyl	RCV000018527	SCV000487401	pathogenic	Deafness, autosomal recessive 1A	2016-03-08	criteria provided, single submitter	clinical testing
Counsyl	RCV000411531	SCV000487402	pathogenic	Deafness, autosomal dominant 3a	2016-03-08	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana	RCV000415181	SCV000492685	pathogenic	Bilateral sensorineural hearing impairment	2014-10-01	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana	RCV000146019	SCV000492742	pathogenic	Hearing impairment	2017-01-01	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana	RCV000415367	SCV000492743	pathogenic	Hearing impairment; Bilateral conductive hearing impairment	2015-01-13	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana	RCV000414886	SCV000492744	pathogenic	Hearing impairment; Bilateral sensorineural hearing impairment	2014-04-12	criteria provided, single submitter	clinical testing
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia	RCV000018527	SCV000599723	pathogenic	Deafness, autosomal recessive 1A	2017-05-09	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000080373	SCV000603812	pathogenic	not provided	2017-05-03	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000080373	SCV000613516	pathogenic	not provided	2018-03-16	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV000018527	SCV000698250	pathogenic	Deafness, autosomal recessive 1A	2017-08-08	criteria provided, single submitter	clinical testing	Variant summary: The GJB2 c.35delG (p.Gly12Valfs) variant results in a premature termination codon, predicted to cause a truncated or absent GJB2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g., c.71G>A [p.Trp24X], c.131G>A [p.Trp44X], and c.167delT [p.Leu56fs). This variant was found in 733/122042 control chromosomes (3 homozygotes) including ExAC at a frequency of 0.0060061, which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.025). This variant is known to be the most common pathogenic GJB2 variant worldwide that causes autosomal recessive nonsyndromic hearing loss. Immunochemistry studies showed that the variant does not produce detectable protein and prevents normal intercellular molecular transfer (D'Andrea_BBRC_2002). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Ambry Genetics	RCV000623840	SCV000741869	pathogenic	Inborn genetic diseases	2014-09-07	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000018527	SCV000746336	pathogenic	Deafness, autosomal recessive 1A	2018-08-07	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000018527	SCV000915629	pathogenic	Deafness, autosomal recessive 1A	2018-12-04	criteria provided, single submitter	clinical testing	The GJB2 c.35delG (p.Gly12ValfsTer2) variant, which results in a frameshift and is predicted to result in premature termination of the protein, is one of the most common variants associated with the recessive form of nonsyndromic hearing loss, DFNB1, with more than half of all persons of northern European ancestry with two identifiable GJB2 mutations being homozygous for this variant (Scott et al. 1998). Across a small selection of the available literature, the p.Gly12ValfsTer2 variant has been identified in a homozygous state in 89 individuals with hearing loss, in a compound heterozygous state in 23 affected individuals, and in a heterozygous state in 11 affected individuals in whom a second variant was not identified (Zelante et al. 1997; Estivill et al. 1998; Murgia et al. 1999; Snoeckx et al. 2005). The p.Gly12ValfsTer2 variant was identified in a total of ten of 800 control chromosomes and is reported at a frequency of 0.0152 in the Utah residents with Northern and Western European ancestry population of the 1000 Genomes Project which is consistent with the carrier frequency for p.Gly12ValfsTer2 (Snoeckx et al. 2005). Based on the potential impact of frameshift variants and the evidence from the literature the p.Gly12ValfsTer2 variant is classified as pathogenic for recessive nonsyndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000018527	SCV000928370	pathogenic	Deafness, autosomal recessive 1A	2018-06-26	criteria provided, single submitter	clinical testing	PVS1, PS3, PM1, PP5
Invitae	RCV000080373	SCV000950817	pathogenic	not provided	2019-01-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gly12Valfs*2) in the GJB2 gene. It is expected to result in an absent or disrupted protein product. This variant has been reported to segregate with hearing loss in several families (PMID: 9285800, 9328482), and is considered to be a founder mutation in the European population (PMID: 10751669, 12172392, 12176036, 12239718, 19925344). ClinVar contains an entry for this variant (Variation ID: 17004). An experimental study has shown that this frameshift disrupts in GJB2 protein expression and function in cell culture (PMID: 12176036). For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000018527	SCV000038809	pathogenic	Deafness, autosomal recessive 1A	2012-10-05	no assertion criteria provided	literature only
OMIM	RCV000018528	SCV000038810	pathogenic	Deafness, digenic, GJB2/GJB6	2012-10-05	no assertion criteria provided	literature only
GeneReviews	RCV000018527	SCV000041047	pathologic	Deafness, autosomal recessive 1A	2011-07-14	no assertion criteria provided	curation	Converted during submission to Pathogenic.
Division of Human Genetics,Children's Hospital of Philadelphia	RCV000018527	SCV000238466	pathogenic	Deafness, autosomal recessive 1A	2015-03-20	no assertion criteria provided	research	The GJB2 variant (c.35delG, p.Gly12Valfs*2) identified in this patient is a frameshift variant, reported to be the most common pathogenic variant in individuals with European ancestry (Carrasquillo et al. 1997, PMID: 9328482; Denoyelle et al. 1997, PMID: 9336442; Zelante et al. 1997, PMID: 9285800; Green et al. 1999, PMID: 10376574; Gasparini et al. 2000, PMID: 10713883; Kenneson et al. 2002, PMID: 12172392; Bouwer et al. 2007, PMID: 18294064).
Centre for Mendelian Genomics,University Medical Centre Ljubljana	RCV000415175	SCV000492702	pathogenic	Severe sensorineural hearing impairment	2016-01-04	no assertion criteria provided	clinical testing
Division of Human Genetics,Children's Hospital of Philadelphia	RCV000477882	SCV000536698	pathogenic	Deafness, autosomal recessive 1A; Mutilating keratoderma; Hystrix-like ichthyosis with deafness; Keratitis-ichthyosis-deafness syndrome, autosomal dominant; Keratoderma palmoplantar deafness; Knuckle pads, deafness AND leukonychia syndrome; Deafness, autosomal dominant 3a	2014-10-31	no assertion criteria provided	research
GenomeConnect, ClinGen	RCV000509532	SCV000606924	not provided	Deafness		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
GenomeConnect, ClinGen	RCV000509463	SCV000607350	not provided	Nonsyndromic Hearing Loss, Recessive		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital	RCV000678860	SCV000805053	pathogenic	Hearing loss	2017-02-22	no assertion criteria provided	clinical testing
Center for Statistical Genetics, Columbia University	RCV000146019	SCV000853303	pathogenic	Hearing impairment	2018-11-22	no assertion criteria provided	research
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery,Institute of Otolaryngology, Chinese PLA General Hospital	RCV000018527	SCV000902318	pathogenic	Deafness, autosomal recessive 1A	2019-02-26	no assertion criteria provided	case-control