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]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_004004.6(GJB2):c.107T>C (p.Leu36Pro)

CA172208

158604 (ClinVar)

Gene: GJB2
Condition: nonsyndromic genetic deafness
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: e657ec2a-42b6-42fd-94ab-817fd6805f5d
Approved on: 2022-01-18
Published on: 2024-03-28

HGVS expressions

NM_004004.6:c.107T>C
NM_004004.6(GJB2):c.107T>C (p.Leu36Pro)
NC_000013.11:g.20189475A>G
CM000675.2:g.20189475A>G
NC_000013.10:g.20763614A>G
CM000675.1:g.20763614A>G
NC_000013.9:g.19661614A>G
NG_008358.1:g.8501T>C
ENST00000382844.2:c.107T>C
ENST00000382848.5:c.107T>C
ENST00000382844.1:c.107T>C
ENST00000382848.4:c.107T>C
NM_004004.5:c.107T>C
More

Likely Pathogenic

Met criteria codes 2
PP3 PM3_Very Strong
Not Met criteria codes 19
PS1 PS3 PP2 PP4 PM2 PM1 PM5 PM4 BA1 PVS1 BS2 BS1 BS3 BP5 BP7 BP4 BP3 BP1 BP2

Evidence Links 3

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CDH23, COCH, GJB2, KCNQ4, MYO6, MYO7A, SLC26A4, TECTA and USH2A Version 2

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Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Hearing Loss VCEP
The NM_004004.6:c.107T>C variant in the GJB2 gene is a missense variant predicted to cause substitution of leucine by proline at amino acid 36 (p.Leu36Pro). The highest population minor allele frequency of the variant is 0.01% (2/19954) in the East Asian population in gnomAD v.2.1.1, which does not meet any population codes based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (BA1/BS1/PM2_Supporting not met). The REVEL computational prediction analysis tool produced a score of 0.945, which is above the threshold necessary to apply PP3. This variant has been detected in trans with a pathogenic variant in three patients with hearing loss (4 points, PM3_VeryStrong; PMID:16125251, 16467727, 29605365, 31246659, Invitae internal date (SCV002241983.2)). The variant has also been reported in five individuals with no pathogenic variant reported in trans (PMIDs:17666888, 26043044, 31581539, 31992338). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive hearing loss. ACMG/AMP criteria applied as specified by the ClinGen Hearing Loss VCEP: PM3_VeryStrong, PP3 (ClinGen Hearing Loss VCEP specifications version 2; 1/18/2022).
Met criteria codes
PP3
REVEL score in 0.945
PM3_Very Strong
This variant has been detected in trans with a pathogenic variant in three patients with hearing loss (4 points, PM3_VeryStrong; PMID:16125251, 16467727, 29605365, 31246659, Invitae internal date (SCV002241983.2)).
The p.Leu36Pro variant was found in trans with a c.79G>A (p.Val27Ile) and a c.341A>G (p.Glu114Gly) variant, in a Han Chinese hearing loss patient. Both variants found in trans are at high frequency in gnomAD and have been repeatedly reported as Benign in ClinVar. PubMed:26043044
The p.L36P variant was found in two North American individuals with unspecified hearing loss. No variant was identified in trans PubMed:17666888
Of 65 nonsyndromic pediatric cochlear implant patients with severe to profound hearing loss, the p.L36P variant was found in one African proband in trans with the 35delG variant. Four total African ethnicity probands were included in this study. PubMed:16125251
Not Met criteria codes
PS1
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
PP2
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
The highest population minor allele frequency of the variant is 0.01% (2/19954) in the East Asian population in gnomAD v.2.1.1, which does not meet any population codes
PM1
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
BA1
The highest population minor allele frequency of the variant is 0.01% (2/19954) in the East Asian population in gnomAD v.2.1.1, which does not meet any population codes
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
The highest population minor allele frequency of the variant is 0.01% (2/19954) in the East Asian population in gnomAD v.2.1.1, which does not meet any population codes
BS3
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
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
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
The p.Leu36Pro variant was found in trans with a c.79G>A (p.Val27Ile) and a c.341A>G (p.Glu114Gly) variant, in a Han Chinese hearing loss patient. Both variants found in trans are at high frequency in gnomAD and have been repeatedly reported as Benign in ClinVar. PubMed:26043044
The p.L36P variant was found in two North American individuals with unspecified hearing loss. No variant was identified in trans PubMed:17666888
Of 65 nonsyndromic pediatric cochlear implant patients with severe to profound hearing loss, the p.L36P variant was found in one African proband in trans with the 35delG variant. Four total African ethnicity probands were included in this study. PubMed:16125251
Curation History
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