NM_004004.6(GJB2):c.34G>T (p.Gly12Cys) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Jan 21, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000080371.41

Allele description [Variation Report for NM_004004.6(GJB2):c.34G>T (p.Gly12Cys)]

NM_004004.6(GJB2):c.34G>T (p.Gly12Cys)

Gene:

GJB2:gap junction protein beta 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

13q12.11

Genomic location:

Preferred name:

NM_004004.6(GJB2):c.34G>T (p.Gly12Cys)

Other names:

NM_004004.5(GJB2):c.34G>T(p.Gly12Cys); NM_004004.5(GJB2):c.34G>T; NM_004004.6(GJB2):c.34G>T

HGVS:

NC_000013.11:g.20189548C>A
NG_008358.1:g.8428G>T
NM_004004.6:c.34G>TMANE SELECT
NP_003995.2:p.Gly12Cys
NP_003995.2:p.Gly12Cys
LRG_1350t1:c.34G>T
LRG_1350:g.8428G>T
LRG_1350p1:p.Gly12Cys
NC_000013.10:g.20763687C>A
NM_004004.5:c.34G>T
c.34G>T
p.GLY12CYS

Protein change:

G12C

Links:

dbSNP: rs104894408

NCBI 1000 Genomes Browser:

rs104894408

Molecular consequence:

NM_004004.6:c.34G>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000112268	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Likely pathogenic (Sep 28, 2017)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 15365987, 17041943, 17666888 Citation Link,
SCV000321724	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Dec 15, 2021)	germline	clinical testing	Citation Link,
SCV000603834	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021)	Likely pathogenic (Jul 30, 2021)	germline	clinical testing	Citation Link,
SCV000613514	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Likely pathogenic (Sep 9, 2021)	unknown	clinical testing	PubMed (10) [See all records that cite these PMIDs] 17041943, 17666888, 20154630, 31163360, 31035178, 15365987, 25262649, 25288386, 26252218, 26467025
SCV001095617	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jan 21, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 20154630, 26969326, 31163360, 28492532

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	11	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

DNA sequence analysis of GJB2, encoding connexin 26: observations from a population of hearing impaired cases and variable carrier rates, complex genotypes, and ethnic stratification of alleles among controls.

Tang HY, Fang P, Ward PA, Schmitt E, Darilek S, Manolidis S, Oghalai JS, Roa BB, Alford RL.

Am J Med Genet A. 2006 Nov 15;140(22):2401-15. Erratum in: Am J Med Genet A. 2008 Nov 15;146A(22):2979..

PubMed [citation]

PMID:: 17041943
PMCID:: PMC3623690

A multicenter study of the frequency and distribution of GJB2 and GJB6 mutations in a large North American cohort.

Putcha GV, Bejjani BA, Bleoo S, Booker JK, Carey JC, Carson N, Das S, Dempsey MA, Gastier-Foster JM, Greinwald JH Jr, Hoffmann ML, Jeng LJ, Kenna MA, Khababa I, Lilley M, Mao R, Muralidharan K, Otani IM, Rehm HL, Schaefer F, Seltzer WK, Spector EB, et al.

Genet Med. 2007 Jul;9(7):413-26.

PubMed [citation]

PMID:: 17666888

See all PubMed Citations (12)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000112268.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	11	not provided	not provided	clinical testing	PubMed (3)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		11	not provided	not provided	not provided

From GeneDx, SCV000321724.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Reported in published literature in the heterozygous state in multiple unrelated individuals with congenital hearing loss (Azaiez et al., 2004; Tang et al., 2006; Hernndez-Jurez et al. 2014); Observed in two heterozygous individuals who reported a family history suggestive of autosomal dominant hearing loss, but no segregation studies were performed for the p.(G12C) variant (Tang et al., 2006; Sloan-Heggen et al., 2016); 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: 25262649, 17666888, 25388846, 26969326, 26444186, 15365987, 25288386, 18987669, 26252218, 11912510, 22643125, 22011219, 31163360, 31160754, 30275481, 20154630, 17041943)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000603834.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The c.34G>T p.Gly12Cys variant (rs104894408) is reported in the literature in multiple hearing loss patients (Putcha 2007, Tang 2006, Hernandez-Juarez 2014, Shen 2019). Testing performed at ARUP Laboratories has identified two individuals with hearing loss who carry p.Gly12Cys on the opposite chromosome from a known pathogenic GJB2 variant and a third affected individual homozygous for the p.Gly12Cys variant. In addition, two other variants at this same amino acid (p.Gly12Val, p.Gly12Asp) have been reported in individuals with autosomal recessive nonsyndromic hearing loss and are considered pathogenic (Putcha 2007, Hernandez-Juarez 2014). The glycine at codon 12 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL:0.838). Based on available evidence, the p.Gly12Cys variant is considered to be likely pathogenic. References: Hernandez-Juarez AA et al. GJB2 and GJB6 mutations are an infrequent cause of autosomal-recessive nonsyndromic hearing loss in residents of Mexico. Int J Pediatr Otorhinolaryngol. 2014 Dec;78(12):2107-2012. Putcha et al. 2007. A multicenter study of the frequency and distribution of GJB2 and GJB6 mutations in a large North American cohort. Genet. Med. 9(7):413-26. Tang et al. 2006. DNA sequence analysis of GJB2, encoding connexin 26: observations from a population of hearing impaired cases and variable carrier rates, complex genotypes, and ethnic stratification of alleles among controls. Am. J. Med. Genet. A. 140(22):2401-15. Shen J et al. ClinGen Hearing Loss Working Group. Consensus interpretation of the p.Met34Thr and p.Val37Ile variants in GJB2 by the ClinGen Hearing Loss Expert Panel. Genet Med. 2019 Nov;21(11):2442-2452. PMID: 31160754.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Athena Diagnostics, SCV000613514.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001095617.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 12 of the GJB2 protein (p.Gly12Cys). This variant is present in population databases (rs104894408, gnomAD 0.4%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with autosomal recessive nonsyndromic sensorineural deafness (PMID: 20154630, 26969326, 31163360; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 44740). 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%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 3, 2024

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