The GJB2 NM_004004.6:c.109G>A (NP_003995.2:p.(Val37Ile)) missense variant has previously been reported in somatic cancers (COSMIC; COSV109720373, n = 1 time). Experimental evidence: V37I conductance was 0.013 ± 0.003 µS versus 0.023 ± 0.006 µS water control and 3.646 ± 0.817 µS wild type. Based on available guidelines, this variant is considered to be a Variant of Uncertain Significance (VUS). This variant is considered to be Pathogenic by the VCEP (ClinGen Hearing Loss Variant Curation Expert Panel; ClinVar ID 17023).
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.GJB2 encodes connexin 26, a member of the gap junction protein family. Connexins assemble into hexameric channels in the plasma membrane that regulate the passage of ions and small molecules between cells and, when joined between adjacent cells, form intercellular gap junction channels that allow direct cell-to-cell communication. Mutations in this gene are responsible for up to 50% of pre-lingual, recessive deafness. No established role in cancer is described.
The recorded framework is ClinGen GJB2 VCEP v2.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
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.
Met Strong: p.Val37Ile homozygotes were enriched in cases versus controls, OR 20 with 95% CI 17-24 and p < 0.0001.
Met, Strong: p.V37I was reported in two affected compound-heterozygous probands, satisfying the VCEP's two-proband trans-phase example.
Met at strong: at least 21 affected siblings carried the same biallelic p.Val37Ile genotypes as hearing-loss probands, exceeding the three-relative threshold.
Not applicable: the VCEP explicitly excludes PP5 from use, regardless of the ClinGen consensus classification.
Met: gnomAD v2.1 all-comers MAF 0.75559% exceeds the VCEP autosomal-recessive BA1 threshold of 0.5%.
Met at strong: gnomAD v2.1 all-comers MAF 0.75559% exceeds the VCEP BS1 autosomal-recessive threshold of 0.3%.
Met, Supporting: p.V37I was reported in cis with pathogenic dominant p.R75Q in one Korean patient, satisfying the VCEP's BP2 cis criterion.
VUS: PS4 strong plus PM3 strong satisfy a Pathogenic rule, while BA1 satisfies the stand-alone Benign rule, producing conflicting evidence under the VCEP's ACMG/AMP base rules.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 4,071 / 1,613,686 alleles. Recorded AF 0.0025228. Recorded homozygote count 101.
This variant is present in gnomAD v2.1 (AF= 0.00755589; MAF= 0.75559%, 2132/282164 alleles, homozygotes = 99) and has highest observed frequency in the East Asian population (AF= 0.0834503; MAF= 8.34503%, 1665/19952 alleles, homozygotes = 96); grpmax FAF= 0.0795343.
Not available in gnomAD-Canada v1.0.
Recorded REVEL score: 0.656. Refer to the recorded PP3/BP4 rationale for interpretation.
48 Pathogenic · 4 Likely pathogenic · 1 Uncertain significance · 1 Pathogenic, low penetrance · 1 LIKELY PATHOGENIC · 1 pathogenic. ClinVar API review status: reviewed by expert panel.
No standalone functional evidence summary is recorded in evidence_summary.functional.
This variant has previously been reported in somatic cancers (COSMIC; COSV109720373, n = 1 times).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under ClinGen GJB2 VCEP v2.0, with the data and sources behind each one.
28 criteria with recorded statuses: 8 met · 7 not met · 5 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Among the requested codon, residue, domain, and missense-mechanism criteria, PS1, PM1, and PM5 are not met; PP2 and BP1 are not applicable under the VCEP.
No criterion in this group contributes evidence to the variant classification.
Within the requested segregation/de novo criteria, PP1 is met at Supporting strength; PS2 and PM6 are not met because the queried p.Val37Ile allele is not documented as de novo; BS4 is not assessed because reduced or incomplete penetrance is reported and qualifying non-segregation is not established.
PS3 is met at Moderate strength because validated GJB2 electrical-coupling assays show V37I function at negative-control/background levels rather than wild-type levels; BS3 is not met because the same exact-variant data demonstrate deleterious functional effects.
PS4 is met at Strong from direct case-control enrichment in the VCEP's specified statistical path.
PP4 is not assessed because the required VCEP Table 7 phenotype-specificity specification is unavailable.
PP5 and BP6 are not applicable because the VCEP excludes both criteria.
BP5 is not applicable because the VCEP excludes BP5 for autosomal recessive disease, the GJB2 disease framework here.
Allelic evidence supports both pathogenic recessive inheritance and the VCEP's cautious benign BP2 observation because the case literature contains distinct trans compound-heterozygous and cis dominant-variant observations; these criteria are reported independently as requested.
Population evidence supports BA1 and BS1_Strong because the gnomAD v2.1 all-comers frequency exceeds both VCEP autosomal-recessive thresholds.
PM2 is not met because the variant is substantially more common than the VCEP autosomal-recessive rarity cutoff.
BS2 is not assessed because population homozygote counts lack unaffected-control phenotype and biallelic-with-known-pathogenic-variant documentation.
No criteria match.
PS3_Moderate is met under the Hearing Loss VCEP rule for validated GJB2 electrical coupling assays. The exact p.Val37Ile (c.109G>A) construct was tested in paired Xenopus laevis oocytes using two-electrode voltage clamp. In Bruzzone et al. (PMID:12505163), junctional conductance was 0.013 ± 0.003 µS in 15 V37I oocyte pairs, comparable to the water-injected negative control (0.023 ± 0.006 µS) and markedly below wild-type HCx26 (3.646 ± 0.817 µS), supporting a deleterious effect with the required negative and wild-type controls. Independent functional work also reports a totally defective V37I hemichannel phenotype and reduced current on coexpression with wild-type Cx26 (PMID:16300957), while the multicenter consensus study reports no conductance above background and impaired dye transfer for p.Val37Ile (PMID:31160754). The VCEP specifically calibrates these validated GJB2 electrical coupling and dye-transfer findings to PS3_Moderate; the V37I result satisfies the electrical-coupling path.
Validated functional studies show a deleterious effect (predefined list): GJB2: electrical coupling assays, dye transfer assays → PS3_Moderate * Electrical Coupling Assays: Expect results comparing the current of the variant-transfected cells to both a negative control (i.e. H2O injected control) and a wildtype-transfected cell. PS3_Moderate would be applied if the variant results in significantly different current compared to the wildtype, and the current is comparable to background levels/negative control.
Met at Strong. The VCEP rule is satisfied by statistically significant case-control enrichment. The ClinGen Hearing Loss Expert Panel study explicitly defined affected individuals as cases and carrier-screening individuals as population controls, performed 2 x 2 case-control analyses, and reported p.Val37Ile homozygotes enriched in cases with OR 20 (95% CI 17-24, p < 0.0001) overall and OR 12 (95% CI 9.1-15, p < 0.0001) in Asians; compound heterozygotes plus homozygotes had OR 19 (95% CI 15-24, p < 0.0001) in Asians. The confidence intervals exclude 1, so this is a statistical increase in cases over controls under the VCEP's Strong rule. The independent meta-analysis also reported OR 7.14 (95% CI 3.01-16.95) for p.V37I homozygotes and OR 3.63 (95% CI 1.38-9.54) for compound heterozygotes. The literature_pass papers already classified as PS4 were checked against their available abstract/full text: PMID:28489599 and PMID:31160754 directly support case-control enrichment; PMID:17935238 reports significant overrepresentation in affected individuals versus approximately 1,000 controls in its abstract, but no source_registry key or fetched full text is available for citation. No numeric operator is specified in the VCEP PS4 rule; the applicable rule requires a statistical increase, which the reported case-control results demonstrate.
Fisher Exact or Chi-Squared analysis shows statistical increase in cases over controls, OR...Autosomal dominant: ≥15 probands with variant, and variant meets PM2_Supporting.
GJB2 is specified as an autosomal-recessive hearing-loss gene. The p.V37I variant was reported in two affected probands as compound heterozygous with another pathogenic GJB2 allele, which is evidence of trans phase for the recessive disorder. The VCEP assigns 2 points, and therefore Strong PM3, when the variant is detected in trans in 2 probands with a pathogenic variant.
2 points awarded from tables 7a and 7b Example: Detected in trans in 2 probands with a pathogenic variant (recessive).
The variant-specific segregation evidence reports that p.Val37Ile segregated with hearing loss in families and includes at least 21 affected siblings with the same homozygous or compound-heterozygous p.Val37Ile genotypes as probands. This exceeds the VCEP strong-level recessive threshold of three affected relatives. The phenotype is consistent with GJB2-related hearing loss, although the paper also documents variable expressivity and incomplete penetrance.
Segregation in three affected relatives for recessive and five affected relatives for dominant.
Expert panel ClinGen Hearing Loss Variant Curation Expert Panel classified as Pathogenic.
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
The governing VCEP specifies BA1 at an autosomal-recessive MAF of at least 0.005. Using the default all-comers population entries because the VCEP does not require a non-cancer or exome-only source, gnomAD v2.1 reports 2132/282164 alleles (AF 0.00755589; MAF 0.75559%), which exceeds 0.005. gnomAD v4.1 independently reports AF 0.0025227956, below the threshold, but does not negate the qualifying observed all-comers frequency in gnomAD v2.1.
MAF of ≥0.005 (0.5%) for autosomal recessive; MAF of ≥0.001 (0.1%) for autosomal dominant.
The governing VCEP specifies BS1_Strong at an autosomal-recessive MAF of at least 0.003, provided there is no conflicting evidence. Using the default all-comers population entries because the VCEP does not require a non-cancer or exome-only source, gnomAD v2.1 reports AF 0.00755589 (MAF 0.75559%), exceeding 0.003. The available population frequency therefore meets the VCEP strong threshold; the VCEP's no-conflicting-evidence condition is not contradicted by the population data evaluated here.
MAF of ≥0.003 (0.3%) for autosomal recessive; MAF of ≥0.0002 (0.02%) for autosomal dominant. Likely benign, provided there is no conflicting evidence.
The exact p.V37I variant was reported in cis with the pathogenic dominant GJB2 p.R75Q variant in a Korean patient; the paper's abstract states that the R75Q cis mutation with V37I arose de novo in the father and was inherited by the patient. This directly satisfies the VCEP's BP2 cis-pathogenic-variant pathway, with the VCEP caution noted for GJB2's recessive and dominant disease mechanisms.
Observed in trans with a dominant variant/observed in cis with a pathogenic variant (use with caution). Use with caution. For genes that are associated with both dominant and recessive hearing loss, consider whether an earlier onset/more severe phenotype could be present if variant is identified in trans with a dominant variant.
The variant is GJB2 c.109G>A, p.Val37Ile. The VCEP requires the same amino-acid change as an established pathogenic variant, which would require a qualifying pathogenic comparator with a different nucleotide change producing p.Val37Ile. The case evidence identifies the queried c.109G>A variant itself as expert-panel Pathogenic, but provides no distinct alternate-nucleotide p.Val37Ile comparator; therefore PS1 is not met.
Same amino acid change as an established pathogenic variant; OR splice variants at same nucleotide and with similar impact prediction as previously reported pathogenic variant. * Established variant must meet criteria for pathogenicity by the HL specifications
The available variant-specific family report does not establish a de novo occurrence of GJB2 c.109G>A/p.Val37Ile. In the reported Korean family, the p.Val37Ile allele was inherited by the patient; the de novo event was the different p.Arg75Gln allele in the father. Therefore, no proven de novo occurrence of the queried variant is available for PS2.
4 points per tables 5a and 5b: Examples: 2 proven de novo occurrences; OR 1 proven + 2 assumed de novo occurrences; OR 4 assumed de novo occurrences. ... 2 points per tables 5a and 5b: Examples: 1 proven de novo occurrence; OR 2 assumed de novo occurrences. ... 1 point per tables 5a and 5b: Examples: 1 proven de novo occurrence (phenotype consistent but not specific to gene); OR 1 assumed de novo occurrence; OR 2 assumed de novo occurrences (phenotype/gene not specific). ... 0.5 points per tables 5a and 5b: Example: 1 assumed de novo occurrence (phenotype/gene not specific).
The VCEP PM1 specification defines the qualifying region only for KCNQ4 missense variants in amino acids 271-292. This variant is in GJB2 at residue 37; the VCEP materials contain no GJB2 PM1 domain table entry and no GJB2 hotspot route. Therefore the variant does not meet the VCEP's PM1 specification.
Mutational hot spot or well-studied functional domain without benign variation (KCNQ4 pore-forming region). * KCNQ4 (NM_004700.4) gene - missense variants located within amino acids 271-292 can be awarded PM1.
The governing VCEP permits PM2_Supporting for an autosomal-recessive variant absent or present at no more than 0.00007 (0.007%) in population databases. Using the default all-comers entries because the VCEP does not require a non-cancer or exome-only source, gnomAD v2.1 reports AF 0.00755589 (0.75559%) and gnomAD v4.1 reports AF 0.00252280 (0.25228%); both exceed 0.00007. PM2 is therefore not met.
Absent/Rare in population databases (absent or ≤0.00007 (0.007%) for autosomal recessive, ≤0.00002 (0.002%) for autosomal dominant).
The VCEP PM5 rule requires a different pathogenic missense variant at the same codon, with Strong requiring two such variants and Moderate requiring one. The case's same-residue comparator search found zero same-residue candidates and zero expert-panel or non-expert majority pathogenic/likely pathogenic candidates, so no qualifying pathogenic missense comparator is available for residue 37.
Missense change at same codon as two different pathogenic missense variants. * Located at an amino acid residue with known pathogenic variation (at least 2 other variants at the same site meet pathogenic criteria for based on independent data) * Caveat: Assess whether the variants in question could have an impact at the DNA level, such as through splicing impacts. ... Missense change at same codon as another pathogenic missense variant. No changes. Follow recommendations as outlined in ACMG/AMP guidelines and/or Sequence Variant Interpretation working group.
PM6 uses the PS2 framework for assumed de novo observations. The available variant-specific report states that p.Val37Ile was inherited by the patient, while the de novo event involved the different p.Arg75Gln allele in the father. No assumed de novo occurrence of the queried p.Val37Ile variant is documented.
See PS2 above
BS3 is not met because the applicable VCEP GJB2 functional-assay rule requires a study showing no deleterious effect, with mutant electrical coupling or dye transfer comparable to wild type and appropriate negative-control comparison. The available exact-variant assays instead show V37I conductance at background levels or a totally defective hemichannel phenotype, with impaired dye transfer in the independent multicenter study. These results are inconsistent with the benign functional effect required for BS3; the VCEP also states that functional evidence should not be used at strong strength and assigns qualifying GJB2 assays only at supporting strength.
Functional study shows no deleterious effect (predefined list). * Recommend that functional evidence is not used as strong evidence, due to the absence of well-established functional studies for hearing loss genes. * Guidance on functional evidence at supporting level is as follows (see functional spreadsheets attached): * GJB2: electrical coupling assays, dye transfer assays → BS3_Supporting * Dye Transfer Assays: Expect results that compare the fluorescence of a variant-transfected cell to both a negative control (or H2O injected control) and a wildtype-transfected cell. BS2_Supporting can be applied if the variant results in dye transfer comparable to the wildtype. * Electrical Coupling Assays: Expect results comparing the current of the variant-transfected cells to both a negative control (or H2O injected control) and a wildtype-transfected cell. BS2_Supporting would be applied if the variant results in a current comparable to the wildtype.
Scope: this is a missense variant, so the VCEP's PP3 missense path names REVEL with a cutoff of ≥0.7; its alternative splicing path names MaxEntScan, including for predicted cryptic-site creation or native-site disruption. The available REVEL score is 0.656 and does not meet the VCEP cutoff. SpliceAI reports a max delta score of 0.021, but SpliceAI is not the predictor named by this VCEP rule and cannot substitute for MaxEntScan. MaxEntScan evidence is not available, so the alternative PP3 path cannot be evaluated and PP3 is not_assessed rather than assigned from the non-governing SpliceAI result.
REVEL score ≥0.7, or predicted impact to splicing using MaxEntScan. * Use REVEL and MAXENTSCAN. * For missense variants, award PP3 if REVEL score is ≥0.7. * If splicing is predicted to be impacted, either creation of a cryptic splice site, or disruption of a native splice site, award PP3. * For splice variants (except for canonical -/+1 or 2), use MAXENTSCAN. * For -/+ 1 or 2 splice variants, do not use PP3 if you are using PVS1.
Not assessed. The VCEP requires the patient's phenotype to be highly specific for the gene or a fully sequenced gene set and directs the evaluator to specifications in Table 7. The available VCEP materials contain no Table 7 specification for this case, and the available case evidence does not provide a VCEP-defined phenotype-specificity rule or a complete patient phenotype assessment sufficient to apply PP4 without substituting a generic rule.
Patient's phenotype highly specific for gene or fully sequenced gene set (see specifications in Table 7).
The governing VCEP requires observation of the variant biallelic with a known pathogenic variant in controls and inconsistency with disease penetrance. gnomAD reports homozygous observations (99 in v2.1 all-comers and 101 in v4.1 all-comers), but the available population records do not establish that these individuals are phenotypically unaffected controls or show that their observations are inconsistent with penetrance. The criterion therefore cannot be evaluated from the available evidence without substituting an unstated assumption about control phenotype.
Observation of variant (biallelic with known pathogenic variant for recessive) in controls inconsistent with disease penetrance.
No qualifying non-segregation event with documented phenotype consistency, diagnostic audiometry, age of assessment, and genotype is available. In addition, the reviewed V37I evidence reports variable expressivity and incomplete or reduced penetrance, which the VCEP explicitly excludes from BS4 use. Population observations or normal hearing in heterozygous relatives do not establish BS4 non-segregation for this recessive, variably penetrant genotype.
Non-segregation with disease. ... Any evidence for reduced penetrance, do not use BS4
Scope: the VCEP BP4 rule permits benign supporting evidence when computational evidence suggests no impact, using either REVEL ≤0.15 or no splicing impact in MaxEntScan. The available REVEL score is 0.656 and does not meet the ≤0.15 cutoff. SpliceAI reports a max delta score of 0.021, but SpliceAI is not the predictor named by this VCEP rule and cannot substitute for MaxEntScan. MaxEntScan evidence is not available, so BP4 cannot be evaluated from the governing predictor set and is not_assessed.
Computational evidence suggests no impact; REVEL score ≤0.15 or no impact to splicing in MaxEntScan.
The VCEP defines PVS1 for null variants (nonsense, frameshift, canonical +/-1 or 2 splice-site variants, initiation-codon variants, or single/multi-exon deletions) in a gene with established loss of function as a disease mechanism. NM_004004.6:c.109G>A is a missense substitution producing NP_003995.2:p.(Val37Ile) in exon 2, not a null variant, so PVS1 is not applicable.
Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
The VCEP applies PM4 to protein length change caused by an in-frame deletion or insertion outside a repetitive region. NM_004004.6:c.109G>A is a single-nucleotide missense substitution producing p.Val37Ile, with no insertion, deletion, or protein-length change; PM4 is therefore not applicable.
Protein length change due to an in-frame deletion or insertion that are not located in repetitive regions. ... * No changes. Follow recommendations as outlined in ACMG/AMP guidelines and/or Sequence Variant Interpretation working group.
PP2 is explicitly designated Not Applicable for this VCEP, which advises against using it for this hearing-loss VCEP, particularly for autosomal recessive hearing-loss genes such as GJB2.
Not Applicable for this VCEP
BP1 is explicitly designated Not Applicable for this VCEP. The VCEP does not permit this benign missense-in-a-predominantly-truncating-gene criterion in the governed hearing-loss framework.
Not Applicable for this VCEP
The VCEP applies BP3 to in-frame indels in a repeat region without known function. NM_004004.6:c.109G>A is a missense substitution producing p.Val37Ile, not an in-frame indel, so repeat-region context does not make BP3 applicable.
In-frame indels in repeat region without known function. ... No changes. Follow recommendations as outlined in Richard 2015 and/or ClinGen's Sequence Variant Interpretation working group.
Not applicable. GJB2-related nonsyndromic hearing loss is specified as autosomal recessive in the governing VCEP framework, and the VCEP BP5 rule explicitly states not to use BP5 for autosomal recessive disease because an individual may be a carrier with an alternate cause.
Variant in an autosomal dominant gene found in a patient with an alternate explanation....* Autosomal recessive: Do not use. An individual could be carrier of pathogenic variant and have an alternate cause. Therefore, BP5 shouldn’t be used as evidence for benign in this case....* Autosomal dominant: Can use BP5 as outlined by Richards 2015. * Caveat: consider whether multiple pathogenic autosomal dominant variants could cause a more severe phenotype or whether multigenic inheritance is known to occur (example: Bardet-Biedl syndrome).
Not applicable because the VCEP explicitly excludes BP6 from use. A reputable-source benign report therefore cannot be converted into BP6 under this VCEP framework.
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Scope: the VCEP BP7 rule is limited to silent variants with no predicted impact to splicing. NM_004004.6:c.109G>A produces NP_003995.2:p.(Val37Ile) and is a missense variant, so it lies outside BP7's stated variant scope. BP7 is not_applicable without evaluating splice-prediction evidence.
Silent variant with no predicted impact to splicing.
Every interpreted variant in GJB2, mapped onto the exon structure of NM_004004.6. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| East Asian2013 / 44,852 | 0.04590 hom |
| Ashkenazi Jewish228 / 29,584 | 0.0077 |
| Remaining individuals433 / 62,494 | 0.00696 hom |
| Admixed American171 / 60,032 | 0.00281 hom |
| Middle Eastern11 / 6,058 | 0.0018 |
| European (Finnish)106 / 64,030 | 0.0017 |
| European (non-Finnish)1040 / 1,179,624 | 0.000882 hom |
| African/African American55 / 75,030 | 0.000731 hom |
| South Asian14 / 91,070 | 0.000151 hom |
| East Asian1665 / 19,952 | 0.08396 hom |
| Ashkenazi Jewish83 / 10,342 | 0.008 |
| Remaining individuals31 / 7,212 | 0.0043 |
| Admixed American95 / 35,428 | 0.00271 hom |
| European (Finnish)42 / 25,104 | 0.0017 |
| European (non-Finnish)179 / 128,578 | 0.00141 hom |
| African/African American25 / 24,964 | 0.0011 hom |
| South Asian12 / 30,584 | 0.00039 |
This variant is present in gnomAD v4.1 (AF= 0.0025228; MAF= 0.25228%, 4071/1613686 alleles, homozygotes = 101) and has highest observed frequency in the East Asian population (AF= 0.0448809; MAF= 4.48809%, 2013/44852 alleles, homozygotes = 90); grpmax FAF= 0.0432481.
This variant is present in gnomAD v2.1 (AF= 0.00755589; MAF= 0.75559%, 2132/282164 alleles, homozygotes = 99) and has highest observed frequency in the East Asian population (AF= 0.0834503; MAF= 8.34503%, 1665/19952 alleles, homozygotes = 96); grpmax FAF= 0.0795343.
Not available in gnomAD-Canada v1.0.
Scope: this is a missense variant, so the VCEP's PP3 missense path names REVEL with a cutoff of ≥0.7; its alternative splicing path names MaxEntScan, including for predicted cryptic-site creation or native-site disruption. The available REVEL score is 0.656 and does not meet the VCEP cutoff. SpliceAI reports a max delta score of 0.021, but SpliceAI is not the predictor named by this VCEP rule and cannot substitute for MaxEntScan. MaxEntScan evidence is not available, so the alternative PP3 path cannot be evaluated and PP3 is not_assessed rather than assigned from the non-governing SpliceAI result.
REVEL score ≥0.7, or predicted impact to splicing using MaxEntScan. * Use REVEL and MAXENTSCAN. * For missense variants, award PP3 if REVEL score is ≥0.7. * If splicing is predicted to be impacted, either creation of a cryptic splice site, or disruption of a native splice site, award PP3. * For splice variants (except for canonical -/+1 or 2), use MAXENTSCAN. * For -/+ 1 or 2 splice variants, do not use PP3 if you are using PVS1.
Scope: the VCEP BP4 rule permits benign supporting evidence when computational evidence suggests no impact, using either REVEL ≤0.15 or no splicing impact in MaxEntScan. The available REVEL score is 0.656 and does not meet the ≤0.15 cutoff. SpliceAI reports a max delta score of 0.021, but SpliceAI is not the predictor named by this VCEP rule and cannot substitute for MaxEntScan. MaxEntScan evidence is not available, so BP4 cannot be evaluated from the governing predictor set and is not_assessed.
Computational evidence suggests no impact; REVEL score ≤0.15 or no impact to splicing in MaxEntScan.
Scope: the VCEP BP7 rule is limited to silent variants with no predicted impact to splicing. NM_004004.6:c.109G>A produces NP_003995.2:p.(Val37Ile) and is a missense variant, so it lies outside BP7's stated variant scope. BP7 is not_applicable without evaluating splice-prediction evidence.
Silent variant with no predicted impact to splicing.
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.656. BayesDel score = 0.180516.
13 paper records listed. 5 cited in the classification.
In contrast, we have found that the valine to isoleucine substitution at position 37 (V37I), which had been previously described as a polymorphism in a US population where it did not segregate with deafness [52], is devoid of functional activity.
Location Materials and methods, Section 2.2; Results, Section 3.2 and Table 1; Discussion, paragraph beginning "Genetic deafness is one of the most prevalent inherited sensory disorders"
Context Functional expression of human Cx26 constructs in paired Xenopus laevis oocytes, with antisense oligonucleotide suppression of endogenous Xenopus Cx38 and dual-voltage-clamp measurement of junctional conductance; V37I was tested in 15 oocyte pairs.
The p.V37I [c.G > A] mutant a totally defective phenotype. Coexpression of M34TCx26, V37ICx26 or I82MCx26 significantly decreased the wild type Cx26-mediated currents.
Location Results, Mutations; Functional analysis; Discussion, paragraph beginning ‘The second mutation in hearing impaired patients’
Context Heterologous expression of wild-type and mutant Cx26 in Xenopus laevis oocytes followed by two-electrode voltage-clamp electrophysiology; coexpression assays with wild-type Cx26, Cx30, and Cx31; Western blot analysis of total and plasma-membrane expression.
which arose de novo in the father and was inherited by the patient
Location Abstract
Context Single Korean patient/family report with molecular cloning, HEK293T transfection, biochemical coupling, and hemichannel permeability assays.
Overall, there was a significant association between the p.V37I variant and increased risk of developing HL.
Location Results, Pedigree analyses; Results, Meta-analysis on sporadic HL; Discussion
Context Pedigree analysis of seven unrelated families with GJB2 p.V37I; meta-analysis of 33 studies including 14,398 hearing-loss cases and 8,699 controls.
Furthermore, we reported at least 35 affected siblings with the same homozygous or compound heterozygous genotypes as probands, including 16 with p. Met34Thr and 21 with p. Val37Ile (Table S2). ... Therefore, we did not consider hearing individuals with biallelic p. Met34Thr or p. Val37Ile as observations in controls or nonsegregation.
Location Results, Segregation evidence; Results, genotype–phenotype correlation; Discussion, Genotype–phenotype correlation
Context Multicenter study using data from 15 genetic-testing laboratories and clinics; segregation review, case–control analysis, audiology-confirmed phenotype review, and genotype–phenotype analysis of biallelic GJB2 cases.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
This variant is present in gnomAD v4.1 (AF= 0.0025228; MAF= 0.25228%, 4071/1613686 alleles, homozygotes = 101) and has highest observed frequency in the East Asian population (AF= 0.0448809; MAF= 4.48809%, 2013/44852 alleles, homozygotes = 90); grpmax FAF= 0.0432481.
This variant is present in gnomAD v2.1 (AF= 0.00755589; MAF= 0.75559%, 2132/282164 alleles, homozygotes = 99) and has highest observed frequency in the East Asian population (AF= 0.0834503; MAF= 8.34503%, 1665/19952 alleles, homozygotes = 96); grpmax FAF= 0.0795343.
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Pathogenic (48 clinical laboratories) and as Likely pathogenic (4 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as Pathogenic, low penetrance (1 clinical laboratory) and as LIKELY PATHOGENIC (1 clinical laboratory) and as pathogenic (1 clinical laboratory) and as Pathogenic by ClinGen Hearing Loss Variant Curation Expert Panel (expert panel). (ClinVarID = 17023)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.656. BayesDel score = 0.180516.
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV109720373, n = 1 times).
This variant does not lie in a statistically significant hotspot.