Variant: NM_004004.6(GJB2):c.677T>G (p.Val226Gly)

CA6904209

447450 (ClinVar)

Gene: GJB2

Condition: nonsyndromic genetic deafness

Inheritance Mode: Autosomal recessive inheritance

UUID: 2b5171d0-5733-4e05-a77e-5d32d43be312

HGVS expressions

NM_004004.6:c.677T>G
NM_004004.6(GJB2):c.677T>G (p.Val226Gly)
NC_000013.11:g.20188905A>C
CM000675.2:g.20188905A>C
NC_000013.10:g.20763044A>C
CM000675.1:g.20763044A>C
NC_000013.9:g.19661044A>C
NG_008358.1:g.9071T>G
ENST00000382844.2:c.677T>G
ENST00000382848.5:c.677T>G
ENST00000382844.1:c.677T>G
ENST00000382848.4:c.677T>G
NM_004004.5:c.677T>G

Uncertain Significance

• Met criteria codes: PM2

• Not Met criteria codes: BP2 BP3 BP1 BP4 BP5 BP7 BA1 PS4 PS2 PS3 PS1 PM3 PM1 PM4 PM5 PM6 PP1 PP4 PP2 PP3 PVS1 BS2 BS4 BS3 BS1

Expert Panel

Hearing Loss VCEP

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

Evidence submitted by expert panel

Hearing Loss VCEP

The c.677T>G variant in GJB2 is a missense variant predicted to cause substitution of valine to glycine at amino acid 226. The highest population minor allele frequency in gnomAD v2.1.1 is 0.003% (1/35370) in Latino/Admixed American chromosomes, which is below the PM2_Supporting thresholds defined by the ClinGen Hearing Loss Expert Panel (≤0.007%) for autosomal recessive disorders (PM2_Supporting). The computational predictor REVEL gives a score of 0.586 which is neither above nor below the thresholds predicting a damaging or benign impact on USH2A function (no criteria met). It has been reported in the literature in one heterozygous individual with hearing loss; however, a second variant was not identified and there was no reported family history of hearing loss (no criteria met; PMID: 17666888). This variant has been reported by several clinical laboratories in ClinVar as a variant of uncertain significance (ClinVar Variation ID: 447450). Internal laboratory evidence indicates that the variant has been identified in at least three individuals with hearing loss in the heterozygous state without a second GJB2 variant. One individual was reported to have multiple affected relatives; however, segregation data was not available (no criteria met; SCV000613524.1, SCV000731317.1, SCV002817016.1, SCV002179797.2). In summary, this variant is classified as a variant of uncertain significance based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP; PM2_Supporting. The ClinGen Hearing Loss VCEP Specifications Version 2; 09/26/2023.

Met criteria codes

• PM2: This allele is present in 0.003% of Latino alleles which is below the PM2 cutoff of 0.007% for recessive hearing loss.

Not Met criteria codes

• BP2: 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
• BP4: The REVEL score of 0.586 falls in between what is predicted to be pathogenic/benign.
• 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
• BA1: This allele is present in 0.003% of Latino alleles which is below the PM2 cutoff of 0.007% for recessive hearing loss.
• PS4: There are 2 het cases (one with breast or ovarian cancer and one with HL). No mention of HL status in cancer patient.
• 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
• PM3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM1: HLWG only uses this rule for the pore domain of KCNQ4
• PM4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM5: The p.Val226Asp variant is a VUS in ClinVar.
• PM6: 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
• PP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP3: The REVEL score of 0.586 falls in between what is predicted to be pathogenic/benign.
• 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
• BS4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS1: This allele is present in 0.003% of Latino alleles which is below the PM2 cutoff of 0.007% for recessive hearing loss.

Approved on: 2023-09-26

Published on: 2023-10-05