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]
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  • See Evidence submitted by expert panel for details.

Variant: NM_004004.5(GJB2):c.35delG (p.Gly12Valfs)

CA127023

17004 (ClinVar)

Gene: GJB2
Condition: nonsyndromic genetic deafness
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 58892872-8c79-4342-854b-6878c83611db
Approved on: 2018-09-20
Published on: 2019-07-17

HGVS expressions

NM_004004.5:c.35delG
NM_004004.5:c.35del
NM_004004.5(GJB2):c.35delG (p.Gly12Valfs)
NC_000013.11:g.20189552del
CM000675.2:g.20189552del
NC_000013.10:g.20763691del
CM000675.1:g.20763691del
NC_000013.9:g.19661691del
NG_008358.1:g.8429del
NM_004004.6:c.35del
ENST00000382844.1:c.35del
ENST00000382848.4:c.35del

Pathogenic

The Expert Panel has overridden the computationally generated classification - "Benign"
Met criteria codes 4
PM3_Very Strong PVS1 PS4 BA1
Not Met criteria codes 19
PM6 PM2 PM1 PM4 PM5 BS4 BS1 BS2 BP5 BP7 BP3 BP4 BP2 PS2 PS3 PS1 PP4 PP1 PP3

Evidence Links 2

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Hearing Loss VCEP
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.
Met criteria codes
PM3_Very Strong
Over 15 compound hets / homozygotes with other known pathogenic variants in GJB2 reported in Sloan Heggen 2015 (see supplemental table)
PVS1
Only 1 coding exon of this gene, LOF variants are well known mechanism for GJB2-related hearing loss
PS4
In 1 large study (Sloan-Heggen 2015) and in 1 review article/meta-analysis (Tsukada 2015), the allele frequency of the c.35delG variant was statistically higher in individuals with hearing loss compared with individuals in the general population.
3.2% (72/2238) of alleles reported in this study harbored 35delG. Compared this to the European population in gnomAD (0.969%) since this is the highest frequency population. Ran a 2x2 contingency table using this data, and the two-tailed P value is <0.0001. PubMed:26969326
Review article / Meta-analysis that looked at ethnic-specific spectrum of GJB2 mutations. 35delG was most prevalent among all the studies included. 52 studies included in this analysis that met the following criteria: 1. The article was published in a peer-reviewed journal in the English language. 2. The prevalence of the GJB2 and SLC26A4 mutation alleles among all individuals with sensorineural hearing loss was used. 3. All exons and frank regions of all hearing loss probands were sequenced. Hearing Loss: Total European (includes Finnish) Alleles tested: 6964 Number of European 35delG alleles: 2556 % of 35delG alleles: 36.7% gnomAD data: Total European + Finnish Alleles: 1419 Number of European + Finnish 35delG alleles: 148927 Variant + Variant - Total Cases 2078 4886 6964 "Controls" 1419 123456 124875 Total 3497 128342 131839 Chi-square with Yates correction Chi squared equals 21034.585 with 1 degrees of freedom. The two-tailed P value is less than 0.0001 The association between rows (groups) and columns (outcomes) is considered to be extremely statistically significant. PubMed:25999548
BA1
Filtering AF calculated from gnomAD data 0.0092 (1207/124552). BA1 can be applied, however this variant is on the HL exclusion list, so the BA1 code will not contribute to the overall pathogenicity.
Not Met criteria codes
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM2
Filtering AF calculated from gnomAD data 0.0092 (1207/124552). BA1 can be applied, however this variant is on the HL exclusion list, so the BA1 code will not contribute to the overall pathogenicity.
PM1
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
PM5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
Filtering AF calculated from gnomAD data 0.0092 (1207/124552). BA1 can be applied, however this variant is on the HL exclusion list, so the BA1 code will not contribute to the overall pathogenicity.
BS2
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
BP7
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
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
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
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
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
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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