Variant classification summary

NM_004004.6:c.109G>A

GJB2 · NP_003995.2:p.(Val37Ile) · NM_004004.6

GRCh37: chr13:20763612 C>T · GRCh38: chr13:20189473 C>T

Gene: GJB2 Transcript: NM_004004.6

Final call

VUS

PS3 moderate PS4 strong PM3 strong PP1 strong PP5 supporting BA1 stand-alone benign BS1 strong BP2 supporting

Variant details

Gene

GJB2

Transcript

NM_004004.6

Protein

NP_003995.2:p.(Val37Ile)

gnomAD AF

0.0025227956368215378 (v4.1)

ClinVar

Pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 Moderate: p.Val37Ile conductance was at background rather than wild-type levels in validated assays.

2

PS4 Strong: p.Val37Ile was enriched in affected cases with OR 20 and p<0.0001.

3

PM3 Strong: p.Val37Ile occurred in trans with another pathogenic GJB2 allele in two affected probands.

4

PP1 Strong: at least 21 affected siblings carried the same biallelic p.Val37Ile genotypes as probands.

5

PP5 Supporting: the ClinGen Hearing Loss Expert Panel classified the variant as Pathogenic.

6

BA1 stand-alone benign: gnomAD v2.1 MAF 0.75559% exceeds the VCEP recessive threshold of 0.5%.

7

BS1 Strong: gnomAD v2.1 MAF 0.75559% exceeds the VCEP recessive threshold of 0.3%.

8

BP2 Supporting: p.Val37Ile was observed in cis with pathogenic dominant p.Arg75Gln.

Final determination: PS4 Strong plus PM3 Strong satisfies the ACMG/AMP 2015 Pathogenic rule requiring at least two strong criteria, while BA1 satisfies the stand-alone Benign rule; contradictory pathogenic and benign rules therefore yield VUS.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	Not applicable: c.109G>A is a missense substitution producing p.Val37Ile, not one of the VCEP-defined null variant types.	cspec pvs1_variant_assessment
PS1	Not met	Not met: the pathogenic p.Val37Ile evidence is for the queried c.109G>A variant, with no distinct alternate-nucleotide variant producing the same amino-acid change.	cspec clinvar
PS2	Not met	Not met: the reported de novo event was p.Arg75Gln, whereas the queried p.Val37Ile allele was inherited by the patient.	cspec PMID:26088551
PS3	Met	Met at moderate: V37I conductance was 0.013 ± 0.003 µS versus 0.023 ± 0.006 µS water control and 3.646 ± 0.817 µS wild type.	cspec PMID:12505163 PMID:16300957 PMID:31160754
PS4	Met	Met Strong: p.Val37Ile homozygotes were enriched in cases versus controls, OR 20 with 95% CI 17-24 and p < 0.0001.	cspec PMID:28489599 PMID:31160754
PM1	Not met	Not met: the VCEP PM1 region is KCNQ4 residues 271-292, whereas this variant is GJB2 residue 37 and no GJB2 PM1 domain is specified.	cspec
PM2	Not met	Not met: gnomAD v4.1 all-comers AF 0.25228% already exceeds the VCEP PM2 autosomal-recessive cutoff of 0.007%.	cspec gnomad_v2 gnomad_v4
PM3	Met	Met, Strong: p.V37I was reported in two affected compound-heterozygous probands, satisfying the VCEP's two-proband trans-phase example.	cspec PMID:28489599
PM4	N/A	Not applicable: c.109G>A is a single-nucleotide missense substitution with no in-frame insertion, deletion, or protein-length change.	cspec pvs1_variant_assessment
PM5	Not met	Not met: the same-residue search found zero qualifying pathogenic missense comparators at GJB2 residue 37, below the one-variant PM5 Moderate requirement.	cspec pm5_candidates
PM6	Not met	Not met: p.Val37Ile was inherited by the patient, and the reported de novo event involved the different p.Arg75Gln allele.	cspec PMID:26088551
PP1	Met	Met at strong: at least 21 affected siblings carried the same biallelic p.Val37Ile genotypes as hearing-loss probands, exceeding the three-relative threshold.	cspec PMID:28489599 PMID:31160754
PP2	N/A	Not applicable: the VCEP explicitly excludes PP2, advising against its use particularly for autosomal recessive hearing-loss genes.	cspec
PP3	Not assessed	Not assessed: REVEL 0.656 is below the VCEP's ≥0.7 threshold, and MaxEntScan evidence is unavailable.	cspec revel spliceai pvs1_variant_assessment
PP4	Not assessed	Not assessed: the VCEP PP4 rule requires Table 7 phenotype-specificity specifications, which are unavailable for this case.	cspec
PP5	Met	Not applicable: the VCEP explicitly excludes PP5 from use, regardless of the ClinGen consensus classification.	cspec clinvar
BA1	Met	Met: gnomAD v2.1 all-comers MAF 0.75559% exceeds the VCEP autosomal-recessive BA1 threshold of 0.5%.	cspec gnomad_v2 gnomad_v4
BS1	Met	Met at strong: gnomAD v2.1 all-comers MAF 0.75559% exceeds the VCEP BS1 autosomal-recessive threshold of 0.3%.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD reports 99–101 homozygotes but does not establish unaffected control status or inconsistency with disease penetrance.	cspec gnomad_v2 gnomad_v4
BS3	Not met	Not met: V37I conductance was at background rather than comparable to wild type, and independent assays reported a totally defective phenotype and impaired dye transfer.	cspec PMID:12505163 PMID:16300957 PMID:31160754
BS4	Not assessed	Not assessed: V37I has reported variable or incomplete penetrance, and no fully documented phenotype-positive/genotype-negative or genotype-positive/phenotype-negative family member qualifies.	cspec PMID:31160754
BP1	N/A	Not applicable: BP1 is explicitly designated Not Applicable for this VCEP in the governing hearing-loss specifications.	cspec
BP2	Met	Met, Supporting: p.V37I was reported in cis with pathogenic dominant p.R75Q in one Korean patient, satisfying the VCEP's BP2 cis criterion.	cspec PMID:26088551
BP3	N/A	Not applicable: c.109G>A is a missense substitution, not an in-frame indel in a repeat region without known function.	cspec pvs1_variant_assessment
BP4	Not assessed	Not assessed: REVEL 0.656 exceeds the VCEP's ≤0.15 threshold, and MaxEntScan evidence is unavailable.	cspec revel spliceai pvs1_variant_assessment
BP5	N/A	Not applicable: the VCEP says not to use BP5 for autosomal recessive disease, and GJB2 is specified as autosomal recessive here.	cspec
BP6	N/A	Not applicable: the VCEP explicitly excludes BP6 from use, regardless of any reputable-source benign report.	cspec
BP7	N/A	Not applicable: c.109G>A is a missense variant, not a silent variant.	cspec pvs1_variant_assessment

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