Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • See Evidence submitted by expert panel for details.

Variant: NM_004004.5(GJB2):c.167delT (p.Leu56Argfs)

CA172217

17010 (ClinVar)

Gene: GJB2
Condition: nonsyndromic genetic deafness
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: e530bac1-eebd-46fc-a983-e936764ec5dc
Approved on: 2018-09-19
Published on: 2019-07-17

HGVS expressions

NM_004004.5:c.167delT
NM_004004.5:c.167del
NM_004004.5(GJB2):c.167delT (p.Leu56Argfs)
NC_000013.11:g.20189415del
CM000675.2:g.20189415del
NC_000013.10:g.20763554del
CM000675.1:g.20763554del
NC_000013.9:g.19661554del
NG_008358.1:g.8561del
NM_004004.6:c.167del
ENST00000382844.1:c.167del
ENST00000382848.4:c.167del
More

Pathogenic

The Expert Panel has overridden the computationally generated classification - "Benign"
Met criteria codes 3
PM3_Very Strong BA1 PVS1
Not Met criteria codes 20
BS2 BS1 BS4 BP2 BP4 BP3 BP7 BP5 PS3 PS4 PS2 PS1 PP3 PP1 PP4 PM2 PM6 PM4 PM1 PM5

Evidence Links 5

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Hearing Loss VCEP
The filtering allele frequency of the p.Leu56ArgfsX26 variant in the GJB2 gene is 1.4% (165/10106) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), 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 nonsyndromic hearing loss variants (BA1). The ClinGen Hearing Loss Expert Panel believes that the evidence for the pathogenicity of this variant for nonsyndromic hearing loss outweighs the high allele frequency of the variant in population databases. Therefore, the BA1 code will not contribute to the overall classification. The p.Leu56ArgfsX26 variant in GJB2 is predicted to cause a premature stop codon in the only coding exon of the gene, leading to an absent protein in a gene in which loss-of-function is an established disease 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: 24529908, 26096904, 24158611, 9285800, 17666888). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PVS1, PM3_VS, BA1.
Met criteria codes
PM3_Very Strong
Identified in many individuals with hearing loss in trans with another pathogenic variant
10 patients and 11 alleles or 2% representing 6% of the mutated alleles, 1 homozygote,variant in EC1 domain, AR, phenotype severity ranging from moderateto 3 profound bialleic or double het with GJB6, the homozygote was profoundly affected, PubMed:24158611
observed 2.2% frequency (Sicilian) or 3 alleles, 3 cpd het with 35delG (severe-profound) and authors conclude patients haveless severe HL in c.35delG/truncating alteration compound heterozygotes compared to that in the c.35delG homozygotes. PubMed:26096904
1 allele from chr 13 linked NSRD patient, variant result in loss of restriction site, interpreted as likely disease causing, 1 cpd het with 35delG and this variant, PubMed:9285800
carrier rate of 4% in AJ, variant representing 3.6% of GJB2 allelic variants, described in 1 double het with GJB6, reporting variant in 83 alleles (AR) up to 24% white and 7.2% AJ and 2.4 other (ethnic distribution), PubMed:17666888
76-81% in AJ, cohort Iranian/Turkish presumed ARNSHL, describe 1 homozygote, PubMed:24529908
BA1
1.63% AJ highest pop gnomad, 0.093% Euro filtering AF exac, noted that this variant is part of the exclusion list for which BA1 or BS1 does not apply
PVS1
1/1 coding exon, >50 nt from exon-exon junction-predict NMD, single transcript, fs, LOF is mechanism of disease,
observed 2.2% frequency (Sicilian) or 3 alleles, 3 cpd het with 35delG (severe-profound) and authors conclude patients haveless severe HL in c.35delG/truncating alteration compound heterozygotes compared to that in the c.35delG homozygotes. PubMed:26096904
10 patients and 11 alleles or 2% representing 6% of the mutated alleles, 1 homozygote,variant in EC1 domain, AR, phenotype severity ranging from moderateto 3 profound bialleic or double het with GJB6, the homozygote was profoundly affected, PubMed:24158611
1 allele from chr 13 linked NSRD patient, variant result in loss of restriction site, interpreted as likely disease causing, 1 cpd het with 35delG and this variant, PubMed:9285800
76-81% in AJ, cohort Iranian/Turkish presumed ARNSHL, describe 1 homozygote, PubMed:24529908
carrier rate of 4% in AJ, variant representing 3.6% of GJB2 allelic variants, described in 1 double het with GJB6, reporting variant in 83 alleles (AR) up to 24% white and 7.2% AJ and 2.4 other (ethnic distribution), PubMed:17666888
Not Met criteria codes
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
1.63% AJ highest pop gnomad, 0.093% Euro filtering AF exac, noted that this variant is part of the exclusion list for which BA1 or BS1 does not apply
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
10 patients and 11 alleles or 2% representing 6% of the mutated alleles, 1 homozygote,variant in EC1 domain, AR, phenotype severity ranging from moderateto 3 profound bialleic or double het with GJB6, the homozygote was profoundly affected, PubMed:24158611
observed 2.2% frequency (Sicilian) or 3 alleles, 3 cpd het with 35delG (severe-profound) and authors conclude patients haveless severe HL in c.35delG/truncating alteration compound heterozygotes compared to that in the c.35delG homozygotes. PubMed:26096904
1 allele from chr 13 linked NSRD patient, variant result in loss of restriction site, interpreted as likely disease causing, 1 cpd het with 35delG and this variant, PubMed:9285800
carrier rate of 4% in AJ, variant representing 3.6% of GJB2 allelic variants, described in 1 double het with GJB6, reporting variant in 83 alleles (AR) up to 24% white and 7.2% AJ and 2.4 other (ethnic distribution), PubMed:17666888
76-81% in AJ, cohort Iranian/Turkish presumed ARNSHL, describe 1 homozygote, PubMed:24529908
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
HGMD: GJB2:c.167T>C, p.Leu56Pr. Reporting variant in 1 allele (AR) PubMed:17666888
PP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM2
1.63% AJ highest pop gnomad, 0.093% Euro filtering AF exac, noted that this variant is part of the exclusion list for which BA1 or BS1 does not apply
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
HGMD: GJB2:c.167T>C, p.Leu56Pr. Reporting variant in 1 allele (AR) PubMed:17666888
Curation History
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