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.71G>A (p.Trp24Ter)

CA172240

17002 (ClinVar)

Gene: GJB2
Condition: nonsyndromic genetic deafness
Inheritance Mode: Autosomal recessive inheritance
UUID: b207d225-ce97-42b5-b04a-d9d420ada5eb
Approved on: 2018-09-17
Published on: 2019-07-17

HGVS expressions

NM_004004.5:c.71G>A
NM_004004.5(GJB2):c.71G>A (p.Trp24Ter)
NC_000013.11:g.20189511C>T
CM000675.2:g.20189511C>T
NC_000013.10:g.20763650C>T
CM000675.1:g.20763650C>T
NC_000013.9:g.19661650C>T
NG_008358.1:g.8465G>A
NM_004004.6:c.71G>A
ENST00000382844.1:c.71G>A
ENST00000382848.4:c.71G>A
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Pathogenic

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

Evidence Links 4

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.Trp24X variant in the GJB2 gene is 0.38% (137/ 30782) of South Asian 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 likely benign based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BS1). However, 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 BS1 code will not contribute to the overall classification. The p.Trp24X variant in GJB2 is predicted to cause a premature stop codon in the only exon of GJB2 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: 15070423, 24123366, 18941476, 9139825). A knock-in mouse model demonstrates that the p.Trp24X variant leads to the phenotype (PS3; PMID:18941476). 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, PS3, BS1.
Met criteria codes
PM3_Very Strong
Many examples of the W24* variant found in trans with other nonsense or frameshifting GJB2 alleles.

PVS1
Nonsense change.
BS1
Allele frequency 0.055% overall, 0.44% in South Asian - gnomAD On the exclusion list
PS3
PMID 18941476 completed functional studies, and while this variant still allows for the creation of a protein, it gets stuck in cytoplasm and does not get trafficked to the membrane.

Not Met criteria codes
PM2
Allele frequency 0.055% overall, 0.44% in South Asian - gnomAD On the exclusion list
PM6
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
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
BA1
Allele frequency 0.055% overall, 0.44% in South Asian - gnomAD On the exclusion list
BS2
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
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
BP2
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
PS1
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
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
Curation History
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