The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries.
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Variant: NM_004004.6(GJB2):c.34G>T (p.Gly12Cys)
CA172224
44740 (ClinVar)
Gene: GJB2
Condition: nonsyndromic genetic deafness
Inheritance Mode: Autosomal recessive inheritance
UUID: 060eab50-f9a8-40d2-b449-2edd2f54e4f3
HGVS expressions
NM_004004.6:c.34G>T
NM_004004.6(GJB2):c.34G>T (p.Gly12Cys)
NC_000013.11:g.20189548C>A
CM000675.2:g.20189548C>A
NC_000013.10:g.20763687C>A
CM000675.1:g.20763687C>A
NC_000013.9:g.19661687C>A
NG_008358.1:g.8428G>T
ENST00000382844.2:c.34G>T
ENST00000382848.5:c.34G>T
ENST00000382844.1:c.34G>T
ENST00000382848.4:c.34G>T
NM_004004.5:c.34G>T
Likely Pathogenic
The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Conflicting Evidence"Met criteria codes 4
PM3_Very Strong
PP3
PM5
BS1
Not Met criteria codes 22
PS3
PS4
PS2
PS1
BP5
BP7
BP2
BP3
BP1
BP4
PP1
PP4
PP2
BA1
PVS1
PM6
PM2
PM1
PM4
BS2
BS3
BS4
Evidence Links 5
Evidence submitted by expert panel
Hearing Loss VCEP
The c.34G>T (NM_004004.6) in GJB2 is a missense variant predicted to cause the substitution of glycine by cysteine at amino acid 12 (p.Gly12Cys). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0036 (128/35104 alleles) in the Latino/Admixed American population, which is higher than the ClinGen Hearing Loss VCEP threshold (>0.003) for BS1, and therefore meets this criterion (BS1). This is a high enough frequency that, in absence of conflicting data, might warrant a likely benign classification based on the thresholds defined by the ClinGen Hearing Loss VCEP for autosomal recessive hearing loss variants. However, based on the evidence outlined below, the ClinGen Hearing Loss Expert Panel believes that the evidence for the pathogenicity of this variant for nonsyndromic hearing loss outweighs its high allele frequency in population databases. Therefore, the BS1 code will not contribute to the overall classification. This variant has been detected in at least 10 patients with hearing loss. Of those individuals, at least 4 were compound heterozygous or the variant and a pathogenic or likely pathogenic variant was observed in trans and one proband was homozygous for the variant (c.35delG, p.V37I, p.Val198fs, p.Lys122Ile, PMID: 15365987, 17041943, 17666888, 25288386, 26969326, 31035178, SCV000061501.5) (PM3_Very Strong). A different pathogenic missense variant (p.Gly12Val) (ClinVar Variation ID 21387) in the same codon of GJB2 has been classified as likely pathogenic and pathogenic for hearing loss by 7 labs who are in concordance that this variant is LP/P (PM5). The computational predictor REVEL gives a score of 0.838, and the nucleotide is heavily conserved in UCSC, which is above the threshold of 0.7, evidence that correlates with impact to GJB2 function (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive nonsyndromic genetic hearing loss based on the ACMG/AMP criteria applied as specified by the Hearing Loss VCEP: PM3_Very Strong, PM5, PP3, BS1 (ClinGen Hearing Loss VCEP specifications version 2; 10/19/2022)
Met criteria codes
This variant has been detected in at least 10 patients with hearing loss. Of those individuals, at least 4 were compound heterozygous or the variant and a pathogenic or likely pathogenic variant was observed in trans and one was homozygous for the variant (c.35delG, p.V37I, p.Val198fs, p.Lys122Ile, PMID: 15365987, 17041943, 17666888, 25288386, 26969326, 31035178, SCV000061501.5) (PM3_Very Strong)
p.Gly12Arg (ClinVar ID: 21387) has been submitted by literature only as a pathogenic variant in ClinVar by a 0 star submission. The p.Gly12Val variant in GJB2 has been submitted by 10+ labs who are in concordance that this variant is LP/P. While the p.Gly12Arg variant may need more evidence to be considered a path variant by our standards, the p.Gly12Val variant has sufficient evidence to apply PM5 for this variant.
While this variant technically meets the BS1 cutoff 0.36%(128/35104) Latino/Admixed American population, it is on the ClinGen Hearing Loss Expert Panel exclusion list.
Not Met criteria codes
There is no functional evidence for this variant. There is a fair amount of functional evidence for the p.Gly12Arg variant in GJB2 at this codon, but that cannot be counted here.
attempted to use case-control as there are 10 reported alleles in HL cases in the literature out of 21004 total alleles screened
There are 130/271738 alleles in gnomAD with the variant (used the total because all reports were multiethnic) but the graphpad software only allows a denominator of 123456, therefore, 10/21004 was compared to the frequency in the general population equal to that of 130/271738 but with a denominator of 123456. Which equals 59/123456.
The frequency differential between cases and the general population was NOT significant.
78 individuals in cohort w/ congenital HL form Northeastern Mexico. Identified presumably 1 het individual. Other allele not identified. Largely non European but they also have a multiethnic cohort.
PubMed:25288386
Testing of 1294 persons with deafness at Molecular Otolaryngology Research Laboratories identified 1 person carrying only this GJB2 variant in a heterozygous state. There were 88 other individuals who oly had one identified variant. Assumed multiethnic cohort.
PubMed:15365987
Identified the variant in 3 heterozygous cases in a screening of 610 deaf probands. Variant was not found in 294 controls. Clinical info for one proband: Hispanic w/ family history consistent with autosomal dominant hearing loss. Assumed multiethnic cohort as controls have about 150 AA, Hisp., Asian, and Caucasians each.
PubMed:17041943
7401 deaf probands screened. The variant was identified in a heterozygous state in 4 of the individuals. Multiethnic cohort.
PubMed:17666888
One patient with congenital SNHL, reported inheritance was AD, as the variant was in trans with a p.Tyr68Cys variant that is thought to be LB. Cohort is multiethnic
PubMed:26969326
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
There is no functional evidence for this variant. There is a fair amount of functional evidence for the p.Gly12Arg variant in GJB2 at this codon, but that cannot be counted here.
Approved on: 2022-10-19
Published on: 2023-02-02
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