Variant: NM_004004.5(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

Approved on: 2018-09-11

Published on: 2019-07-17

HGVS expressions

NM_004004.5:c.34G>T
NM_004004.5(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_004004.6:c.34G>T

Likely Pathogenic

• Met criteria codes: PM3_Very Strong PM5 BS1 PP3

• Not Met criteria codes: PVS1 PM6 PM2 PM1 PM4 BA1 BS4 BS3 BS2 BP5 BP7 BP4 BP3 BP1 BP2 PS1 PS2 PS3 PS4 PP1 PP2 PP4

Expert Panel

Hearing Loss VCEP

Criteria Specification Information

Evidence submitted by expert panel

Hearing Loss VCEP

The filtering allele frequency of the p.Gly12Cys variant in the GJB2 gene is 0.32% (129/34098) of Latino chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/). 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 Expert Panel for autosomal recessive hearing loss variants (BS1). However, based on the evidence outline 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 patients with hearing loss in trans with at least 4 pathogenic or suspected-pathogenic variants (PM3_VS; Partners LMM internal data SCV000061501.5). The p.Gly12Cys variant has also been reported in the literature in 10 individuals with hearing loss; however, a variant affecting the remaining DFNB1 allele was not reported (PMID: 15365987, 17041943, 17666888, 25288386, 26969326). A different pathogenic missense variant (p.Gly12Val) has been previously identified at this codon of GJB2 which may indicate that this residue is critical to the function of the protein (PM5; ClinVar Variation ID 21387). Computational prediction tools and conservation analysis suggest that the p.Gly12Cys variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PM3_VS, PM5, PP3, BS1.

Met criteria codes

• PM3_Very Strong: While most literature reports have only identified this variant in a heterozygous state without reporting the variant in trans, the LMM has identified this variant in a compound het state with c.35delG, p.V37I, p..Val198fs, p.Lys122Ile variants (4 total cases) which are all pathogenic or LP variants. The variant was also identified in a homozygous case. All individuals had hearing loss.
• PM5: p.Gly12Arg 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 7 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.
• BS1: While this variant technically meets the BS1 cutoff 0.378%(129/34098) Latino, it is on the ClinGen Hearing Loss Expert Panel exclusion list.
• PP3: REVEL prediction higher than 0.7

Not Met criteria codes

• PVS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM6: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM2: While this variant technically meets the BS1 cutoff 0.378%(129/34098) Latino, it is on the ClinGen Hearing Loss Expert Panel exclusion list.
• 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
• BA1: While this variant technically meets the BS1 cutoff 0.378%(129/34098) Latino, it is on the ClinGen Hearing Loss Expert Panel exclusion list.
• BS4: 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.
• 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
• BP4: REVEL prediction higher than 0.7
• BP3: 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
• BP2: 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
• PS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS3: 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.
• PS4: 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.
• PP1: 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
• PP4: GJB2 does not have a specified phenotype associated with it.