Variant classification summary

NM_004004.6:c.235del

GJB2 · NP_003995.2:p.(Leu79CysfsTer3) · NM_004004.6

GRCh37: chr13:20763485 AG>A · GRCh38: chr13:20189346 AG>A

Gene: GJB2 Transcript: NM_004004.6

Final call

VUS

PVS1 very strong PS4 strong PM3 very strong PP5 supporting BA1 stand-alone benign BS1 strong

Variant details

Gene

GJB2

Transcript

NM_004004.6

Protein

NP_003995.2:p.(Leu79CysfsTer3)

gnomAD AF

0.00019143320901532704 (v4.1)

ClinVar

Pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic: PVS1 very strong supports a null GJB2 frameshift in an established loss-of-function mechanism.

2

Pathogenic: PS4 strong shows c.235delC enrichment in affected cases versus controls.

3

Pathogenic: PM3 very strong documents c.235delC in trans with pathogenic p.Val37Ile in 32 cases.

4

Supporting: PP5 records the expert-panel pathogenic classification retained in the adjudicated criteria.

5

Benign: BA1 is met because the gnomAD v4.1 East Asian allele frequency exceeds 0.5%.

6

Benign: BS1 strong is met because the gnomAD v4.1 East Asian allele frequency exceeds 0.3%.

Final determination: Under ACMG/AMP 2015 Table 5 as the VCEP base, the pathogenic rule of one very strong plus one strong criterion and the benign rules of BA1 and at least one strong benign criterion are both satisfied, so the evidence is contradictory and the call is 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	Met	Met, very strong: c.235del is a GJB2 exon-2 frameshift yielding p.(L79Cfs*3), a null premature-termination product in an established loss-of-function mechanism.	cspec pvs1_gene_context pvs1_variant_assessment PMID:31160754
PS1	N/A	Not applicable: c.235del produces p.(Leu79CysfsTer3), a frameshift rather than the VCEP's same-amino-acid missense or same-nucleotide splice routes.	cspec
PS2	Not assessed	Not assessed: no documented proband-parent testing establishes a de novo occurrence or supplies the VCEP-required de novo point count.	cspec clinvar
PS3	Not assessed	Not assessed: functional reports suggest loss of junctional conductance, but required wild-type and negative-control assay results are unavailable.	cspec clinvar PMID:12352684 PMID:12505163
PS4	Met	Met at strong: cases carried c.235delC in 7/40 chromosomes versus 0/100 controls, yielding continuity-corrected OR 46.38 (approximate 95% CI 2.58-834.53).	cspec
PM1	N/A	Not applicable: the VCEP's only specified PM1 region is KCNQ4 amino acids 271-292, whereas this is a GJB2 residue-79 frameshift.	cspec
PM2	Not met	Not met: gnomAD v4.1 all-comers AF is 0.01914%, above the VCEP PM2 autosomal-recessive cutoff of 0.007%.	cspec gnomad_v4 gnomad_v2
PM3	Met	Met at Very Strong: c.235delC was reported in trans with pathogenic p.Val37Ile in 32 cases, exceeding the VCEP example threshold of at least 4 probands.	cspec PMID:31160754
PM4	N/A	Not applicable: c.235del is a frameshift deletion, whereas the VCEP PM4 rule applies only to non-repetitive in-frame insertions or deletions.	cspec pvs1_variant_assessment
PM5	N/A	Not applicable: c.235del causes p.(Leu79CysfsTer3), a frameshift, but PM5 requires a missense change at the same codon.	cspec
PM6	Not assessed	Not assessed: the record lacks the parental and phenotype information needed to establish an assumed de novo occurrence under the VCEP PS2 rule.	cspec clinvar
PP1	Not assessed	Not assessed: no pedigree or genotype data quantify segregation in the one, two, or three affected relatives required by the VCEP thresholds.	cspec clinvar
PP2	N/A	Not applicable: the VCEP excludes PP2 for this gene.	cspec
PP3	N/A	Not applicable: c.235del is a coding frameshift, whereas PP3 covers missense variants with REVEL or splice variants evaluated with MaxEntScan.	cspec
PP4	Not assessed	Not assessed: hearing loss is documented, but the required VCEP Table 7 evidence showing phenotype specificity for GJB2 is unavailable.	cspec
PP5	Met	Not applicable: the VCEP explicitly prohibits use of PP5, regardless of external pathogenic classifications.	cspec clinvar
BA1	Met	Met: gnomAD v4.1 East Asian AF is 0.66628%, exceeding the VCEP autosomal-recessive BA1 threshold of 0.5%.	cspec gnomad_v4 gnomad_v2
BS1	Met	Met at strong: gnomAD v4.1 East Asian AF is 0.66628%, exceeding the VCEP BS1 strong threshold of 0.3% for autosomal-recessive disease.	cspec gnomad_v4 gnomad_v2
BS2	Not met	Not met: gnomAD v4.1 reports 0 homozygotes, so no biallelic control observation demonstrates inconsistency with disease penetrance.	cspec gnomad_v4 gnomad_v2
BS3	Not assessed	Not assessed: no wild-type-comparable functional result is documented, while the available assay lead instead indicates loss of junctional conductance.	cspec clinvar PMID:12352684 PMID:12505163
BS4	Not assessed	Not assessed: no relatives have documented discordant genotype and phenotype with the audiometric and penetrance information required for VCEP non-segregation.	cspec clinvar
BP1	N/A	Not applicable: the VCEP excludes BP1 for this gene.	cspec
BP2	Not met	Not met: the variant was observed in trans with a pathogenic recessive p.Val37Ile, not in trans with a dominant variant or in cis with a pathogenic variant.	cspec PMID:31160754
BP3	N/A	Not applicable: c.235del is a frameshift deletion, not an in-frame indel required by the VCEP BP3 rule.	cspec pvs1_variant_assessment
BP4	N/A	Not applicable: c.235del is a truncating frameshift, so no predicted splice impact cannot provide BP4 evidence of no impact on the gene product.	cspec
BP5	N/A	Not applicable: GJB2 is autosomal recessive here, and the VCEP states not to use BP5 for autosomal-recessive disease.	cspec
BP6	N/A	Not applicable: the VCEP explicitly prohibits use of BP6, regardless of benign reports from reputable sources.	cspec
BP7	N/A	Not applicable: c.235del is a coding frameshift producing p.(L79Cfs*3), not the silent variant required by BP7.	cspec

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