The GJB2 NM_004004.6:c.235del (NP_003995.2:p.(Leu79CysfsTer3)) frameshift variant has previously been reported in somatic cancers (COSMIC; COSV67010611, n = 2 times). 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 17014).
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, 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.
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).
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.
Not applicable: the VCEP explicitly prohibits use of PP5, regardless of external pathogenic classifications.
Met: gnomAD v4.1 East Asian AF is 0.66628%, exceeding the VCEP autosomal-recessive BA1 threshold of 0.5%.
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.
VUS: PVS1 very strong, PS4 strong, and PM3 very strong satisfy a pathogenic rule, while BA1 stand-alone benign and BS1 strong satisfy benign rules, creating contradictory evidence.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 309 / 1,614,140 alleles. Recorded AF 0.000191433. Recorded homozygote count 0.
This variant is present in gnomAD v2.1 (AF= 0.000473847; MAF= 0.04738%, 134/282792 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.00651498; MAF= 0.65150%, 130/19954 alleles, homozygotes = 0); grpmax FAF= 0.00643306.
Not available in gnomAD-Canada v1.0.
Recorded SpliceAI maximum delta score: 0.067. Refer to the recorded PP3/BP4 rationale for interpretation.
36 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; COSV67010611, n = 2 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: 6 met · 3 not met · 7 not assessed · 12 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
The three requested consequence criteria were assessed only under the ClinGen Hearing Loss Expert Panel Version 2.0 specifications: PVS1 is met at very strong strength, while PM4 and BP3 are not applicable because the variant is a frameshift rather than an in-frame indel.
PS4 is met at strong strength from direct case-control enrichment reported for c.235delC/233delC and corroborated by a meta-analysis; PP4 remains not assessed because the VCEP's Table 7 phenotype-specificity requirement is not evaluable; PP5 and BP6 are prohibited by the VCEP; BP5 is excluded for this autosomal-recessive GJB2 context.
PP3 is not applicable because the VCEP scope covers missense or splice variants, not this coding frameshift.
BP4 is not applicable because no predicted splice impact does not negate the truncating protein effect of this frameshift.
BP7 is not applicable because the variant is not silent.
No criteria match.
NM_004004.6:c.235del is a frameshift variant in exon 2 that produces NP_003995.2:p.(L79Cfs*3), a premature termination product. The governing VCEP framework identifies GJB2 as a gene for which PVS1 should be considered and supports very-strong PVS1 for a null variant in a gene with an established loss-of-function disease mechanism. No named VCEP downgrade rule is applicable in the available evidence.
Null variant in a gene with established LOF as a disease mechanism; see PVS1_Strong, PVS1_Moderate, PVS1_Supporting for reduced evidence applications.
The VCEP strong PS4 path is met: Fisher Exact or Chi-Squared analysis shows a statistical increase in cases over controls. Fuse et al. (PMID:10501520) reported the variant as 233delC (the legacy notation for c.235delC) in 7/40 chromosomes from Japanese autosomal-recessive deafness families, versus 0/60 sporadic-deafness chromosomes and 0/100 control chromosomes. This is a case-control comparison even though the paper did not print an odds ratio. Using the 7/40 cases and 0/100 controls, the uncorrected OR is infinite; the Haldane-Anscombe continuity-corrected OR is 46.38 with an approximate 95% CI of 2.58-834.53. The classifier-identified PS4 papers were checked against their available abstract evidence: PMID:10501520 supports the reported counts, and the meta-analysis PMID:22747691 reports significantly higher 235delC frequency in affected individuals than controls, with the abstract identifying a systematic review of 36 papers and 132 studies. The VCEP statistical-increase path does not require a separate numeric OR threshold.
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.
The VCEP awards PM3 Very Strong when 4 points are supported by tables 7a and 7b, with the example of the variant detected in trans in at least 4 probands with a pathogenic recessive variant. PMID:31160754 reports c.235delC, equivalent to NM_004004.6:c.235del, in trans with p.Val37Ile in 32 cases, and the ClinGen Hearing Loss Expert Panel concluded that p.Val37Ile is pathogenic for autosomal recessive nonsyndromic hearing loss. This supplies at least 32 affected cases with the evaluated variant in trans with a pathogenic variant, meeting the VCEP's Very Strong example.
4 points awarded from tables 7a and 7b Example: Detected in trans in ≥4 probands with a pathogenic variant (recessive).
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 Hearing Loss VCEP specifies BA1 at a minor allele frequency (MAF) of ≥0.005 (0.5%) for autosomal recessive disease. GJB2 is autosomal recessive in this VCEP framework. The highest observed all-comers gnomAD v4.1 population frequency is East Asian AF 0.006662804 (299/44,876 alleles; 0.66628%), exceeding 0.005. The all-comers gnomAD v2.1 East Asian AF was also 0.006514984 (130/19,954 alleles; 0.65150%). Therefore BA1 is met.
MAF of ≥0.005 (0.5%) for autosomal recessive; MAF of ≥0.001 (0.1%) for autosomal dominant.
The Hearing Loss VCEP specifies BS1 Strong at a MAF of ≥0.003 (0.3%) for autosomal recessive disease, provided there is no conflicting evidence. GJB2 is autosomal recessive in this VCEP framework. The highest observed all-comers gnomAD v4.1 population frequency is East Asian AF 0.006662804 (0.66628%), exceeding 0.003; the all-comers gnomAD v2.1 East Asian AF was 0.006514984 (0.65150%). No conflicting population observation was identified for applying this frequency rule. Therefore BS1 Strong is met.
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 Hearing Loss VCEP specifies PM2 Supporting for an autosomal recessive variant absent or rare in population databases at AF ≤0.00007 (0.007%). GJB2 is autosomal recessive in this VCEP framework. Using the default all-comers population sources because the VCEP rule does not specify a non-cancer or exome-only source, gnomAD v4.1 reports AF 0.000191433 (309/1,614,140 alleles; 0.01914%), above the PM2 threshold; gnomAD v2.1 reports AF 0.000473847 (134/282,792 alleles; 0.04738%), also above it. The criterion is not met.
Absent/Rare in population databases (absent or ≤0.00007 (0.007%) for autosomal recessive, ≤0.00002 (0.002%) for autosomal dominant).
The Hearing Loss VCEP defines BS2 Strong for observation of the variant biallelic with a known pathogenic variant in controls for recessive disease when that observation is inconsistent with disease penetrance. The available gnomAD observations show zero homozygotes in gnomAD v4.1 all-comers and zero homozygotes in gnomAD v2.1 all-comers; there is no control observation of this variant in a biallelic state with a known pathogenic variant. The BS2 condition is therefore not met.
Observation of variant (biallelic with known pathogenic variant for recessive) in controls inconsistent with disease penetrance. * Advise caution when using this rule, since most of hearing loss is autosomal recessive, and autosomal dominant hearing loss could display reduced penetrance or variable expression. * However, if biallelic observations in controls are inconsistent with disease penetrance, this may be applicable.
The VCEP specifies BP2 for a variant observed in trans with a dominant variant or observed in cis with a pathogenic variant. The available evidence instead documents c.235delC in trans with pathogenic p.Val37Ile in an autosomal recessive GJB2 genotype; it does not show the evaluated variant in trans with a dominant variant or in cis with a pathogenic variant. Therefore BP2 is not met.
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 VCEP PS2 point-based rule cannot be evaluated because the available evidence does not document a proven or assumed de novo occurrence with confirmed or unconfirmed maternity and paternity, nor the required phenotype-specific de novo occurrence count. ClinVar submission metadata includes isolated origin labels such as maternal, germline, inherited, and unknown, but does not provide a proband-parent genotype/phenotype record that establishes de novo status.
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 Hearing Loss VCEP permits PS3_Moderate for GJB2 electrical-coupling or dye-transfer assays showing a deleterious result against both wild-type and negative controls. The available records identify functional studies of 235delC/c.235del, and a ClinVar submission audit describes a truncated GJB2 product unable to facilitate junctional conductance, but the case evidence does not provide the assay data, quantitative result, statistical comparison, or the required wild-type and negative-control results. Therefore the VCEP rule cannot be fully evaluated and PS3 is not assessed.
Validated functional studies show a deleterious effect (predefined list): GJB2: electrical coupling assays, dye transfer assays → PS3_Moderate ... 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. PS3_Moderate would be applied if the variant results in no dye transfer or significantly different dye transfer when compared to the wildtype. ... 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.
The VCEP directs PM6 to the PS2 rule, but the available evidence does not document an assumed de novo occurrence without confirmed maternity and paternity. Origin labels in ClinVar are insufficient to establish an assumed de novo event without the underlying proband-parent testing and phenotype information.
See PS2 above
The VCEP PP1 thresholds require counting affected relatives with segregation for an autosomal recessive disorder. The available evidence does not provide a family pedigree, affected-relative count, genotype results, or documented segregation across meioses, so no PP1 strength can be assigned.
Segregation in three affected relatives for recessive and five affected relatives for dominant. Segregation in two affected relatives for recessive and 4 affected relatives for dominant. Segregation in one affected relative for recessive and two affected relatives for dominant.
The VCEP requires a patient's phenotype highly specific for GJB2 or a fully sequenced gene set, with specifications in Table 7. The available case evidence establishes nonsyndromic hearing loss and GJB2-related observations but does not provide the applicable Table 7 phenotype-specificity entry or demonstrate that the phenotype is sufficiently specific to GJB2 rather than another hearing-loss gene.
Patient's phenotype highly specific for gene or fully sequenced gene set (see specifications in Table 7).
The Hearing Loss VCEP permits BS3_Supporting for GJB2 electrical-coupling or dye-transfer assays showing no deleterious effect, with results comparable to wild-type and assessed against a negative control. The available records do not document a benign or wild-type-comparable result for c.235del; instead, the available ClinVar audit lead describes loss of junctional conductance. Because the complete assay results and required controls are unavailable, the VCEP rule cannot be evaluated to a criterion-level conclusion and BS3 is not assessed.
Functional study shows no deleterious effect (predefined list).
The VCEP BS4 rule cannot be evaluated because the available evidence does not document phenotype-positive/genotype-negative or genotype-positive/phenotype-negative relatives, diagnostic audiometric testing, age and severity consistency, or evidence excluding reduced penetrance and subclinical hearing loss.
Non-segregation with disease. * Phenotype+/genotype- * Strong evidence for benign. * Be cautious when using this as the possibility for phenocopy is high. The hearing loss phenotype should be consistent within the family to consider it a non-segregation, though intra-familial variability has been reported. Factors to consider are: * Age of onset (ie. congenital/early childhood vs. adult onset). * Hearing loss prevalence increases significantly with age. A congenital hearing loss in a child and a late onset hearing loss in a grandparent would not be a consistent phenotype. * Severity (ie - mild vs. profound). * Minor differences may exist among family members. * Keep in mind that progression in older individuals may account for a discrepancy between individuals. * Sex -based differences (infertility, genes on X chromosomes) * Audiogram shape. * May not be completely consistent among family members even with same etiology. * Genotype+/phenotype- * Confounding variables to applying this rule: Age-related/sex-related penetrance, variable expressivity, etc. * If the gene is associated with later onset and individual with the non-segregation is beyond the expected age that the hearing loss would occur, consider applying BS4_Supporting * Recommend only using for fully penetrant genes (typically genes associated with AR hearing loss). * Must be confident that patient is truly unaffected and a hearing loss is not missed or subclinical. Be cautious if only phenotyping was newborn hearing screening. Diagnostic audiometric testing (auditory brainstem response (ABR) or audiogram should be required). * Any evidence for reduced penetrance, do not use BS4
The case variant is NM_004004.6:c.235del, normalized as NP_003995.2:p.(Leu79CysfsTer3), a frameshift. It is neither a missense variant producing the same amino-acid change nor a splice variant at the same nucleotide, so neither route in the VCEP PS1 rule applies.
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 * Can also use PS1 for splice variants located in the splice consensus sequence, at the same nucleotide position as a previously reported pathogenic variant * Example: c.105+1G>C is known to be pathogenic, can use PS1 for c.105+1G>T * No additional hearing loss specifications for missense variants. Follow recommendations as outlined in Richard 2015 and/or the Sequence Variant Interpretation working group within ClinGen. * Caveat (from ACMG/AMP guidelines): Assess the possibility that the variant may act directly through the DNA change (e.g. through splicing disruption as assessed by at least computational analysis) instead of through the amino acid change)
The VCEP PM1 specification defines its approved region only for KCNQ4 amino acids 271-292, the pore-forming intramembrane region. This case is GJB2 c.235del, producing a frameshift at residue 79; it is not a KCNQ4 missense variant in the specified region. The case's domain_tables entry is empty, so there is no additional authoritative gene-domain route to evaluate.
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. This region is the pore-forming intramembrane region where many variants that cause autosomal dominant hearing loss are located (Naito et al. 2013, PMID: 23717403; https://www.uniprot.org/uniprot/P56696). There are only two missense variants in this region in gnomAD, each with only single allele (http://gnomad.broadinstitute.org/; rs763326539: 1/33578 Latino chromosomes; rs55737429: 1/111720 European chromosomes).
The VCEP PM4 rule is limited to protein-length changes caused by in-frame deletions or insertions outside repetitive regions. NM_004004.6:c.235del is a frameshift deletion, not an in-frame deletion or insertion, so PM4 does not apply.
Protein length change due to an in-frame deletion or insertion that are not located in repetitive regions.
The VCEP PM5 rule requires a missense change at the same codon as one or more pathogenic missense variants. NM_004004.6:c.235del is normalized as NP_003995.2:p.(Leu79CysfsTer3), a frameshift, so PM5 does not apply and no same-residue missense comparison is valid.
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.
The 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 2.0 marks PP2 as not applicable. The VCEP states: "Advise against using this rule because there are few such genes that this would apply to, particularly genes associated to autosomal recessive hearing loss." NM_004004.6:c.235del in GJB2 is a frameshift variant predicted to produce NP_003995.2:p.(Leu79CysfsTer3). This determination was made deterministically from the VCEP criteria specification, prior to LLM adjudication.
deterministic_prefilter: vcep_not_applicable
The VCEP PP3 rule covers missense variants through REVEL or splice variants through MaxEntScan. NM_004004.6:c.235del is an exonic coding frameshift, NM_004004.6:c.235del (NP_003995.2:p.(L79Cfs*3)), not a missense or splice variant. Therefore PP3 is outside its governing scope. The available SpliceAI max delta score of 0.067 is not used because SpliceAI is not the predictor named by this VCEP rule and the variant is outside the rule's splice-variant path.
REVEL score ≥0.7, or predicted impact to splicing using MaxEntScan. ... For missense variants, award PP3 if REVEL score is ≥0.7. ... For splice variants (except for canonical -/+1 or 2), use MAXENTSCAN.
The 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 2.0 marks BP1 as not applicable. NM_004004.6:c.235del in GJB2 is a frameshift variant predicted to produce NP_003995.2:p.(Leu79CysfsTer3). This determination was made deterministically from the VCEP criteria specification, prior to LLM adjudication.
deterministic_prefilter: vcep_not_applicable
The VCEP BP3 rule is limited to in-frame indels in repeat regions without known function. NM_004004.6:c.235del is a frameshift deletion, so it is outside the variant type named by the rule and BP3 does not apply.
In-frame indels in repeat region without known function.
The VCEP BP4 rule requires computational evidence of no impact using REVEL ≤0.15 or no impact to splicing in MaxEntScan. NM_004004.6:c.235del is a truncating coding frameshift, for which absence of predicted splice impact does not negate the protein-truncating effect. Under the criterion's scope, BP4 is not applicable; the available SpliceAI max delta score of 0.067 cannot establish BP4.
Computational evidence suggests no impact; REVEL score ≤0.15 or no impact to splicing in MaxEntScan.
BP5 is not applicable because GJB2-related nonsyndromic hearing loss is autosomal recessive in this VCEP framework. The VCEP specifically states not to use BP5 for autosomal-recessive disease because a carrier may have an alternate cause of disease; the autosomal-dominant path does not apply.
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.
BP6 is not applicable under this VCEP. The VCEP explicitly states that this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
The VCEP BP7 rule applies to silent variants with no predicted splice impact. NM_004004.6:c.235del is a coding frameshift producing NP_003995.2:p.(L79Cfs*3), not a silent variant. BP7 is therefore outside its governing scope, regardless of the available SpliceAI max delta score of 0.067.
Silent variant with no predicted impact to splicing. ... No changes. Follow recommendations as outlined in Richard 2015 and/or ClinGen's Sequence Variant Interpretation working group.
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 Asian299 / 44,876 | 0.0067 |
| Remaining individuals6 / 62,510 | 9.6e-05 |
| South Asian1 / 91,082 | 1.1e-05 |
| European (non-Finnish)3 / 1,180,028 | 2.5e-06 |
| East Asian130 / 19,954 | 0.0065 |
| Remaining individuals1 / 7,220 | 0.00014 |
| South Asian1 / 30,616 | 3.3e-05 |
| European (non-Finnish)2 / 129,142 | 1.5e-05 |
This variant is present in gnomAD v4.1 (AF= 0.000191433; MAF= 0.01914%, 309/1614140 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.0066628; MAF= 0.66628%, 299/44876 alleles, homozygotes = 0); grpmax FAF= 0.00604155.
This variant is present in gnomAD v2.1 (AF= 0.000473847; MAF= 0.04738%, 134/282792 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.00651498; MAF= 0.65150%, 130/19954 alleles, homozygotes = 0); grpmax FAF= 0.00643306.
Not available in gnomAD-Canada v1.0.
The VCEP PP3 rule covers missense variants through REVEL or splice variants through MaxEntScan. NM_004004.6:c.235del is an exonic coding frameshift, NM_004004.6:c.235del (NP_003995.2:p.(L79Cfs*3)), not a missense or splice variant. Therefore PP3 is outside its governing scope. The available SpliceAI max delta score of 0.067 is not used because SpliceAI is not the predictor named by this VCEP rule and the variant is outside the rule's splice-variant path.
REVEL score ≥0.7, or predicted impact to splicing using MaxEntScan. ... For missense variants, award PP3 if REVEL score is ≥0.7. ... For splice variants (except for canonical -/+1 or 2), use MAXENTSCAN.
The VCEP BP4 rule requires computational evidence of no impact using REVEL ≤0.15 or no impact to splicing in MaxEntScan. NM_004004.6:c.235del is a truncating coding frameshift, for which absence of predicted splice impact does not negate the protein-truncating effect. Under the criterion's scope, BP4 is not applicable; the available SpliceAI max delta score of 0.067 cannot establish BP4.
Computational evidence suggests no impact; REVEL score ≤0.15 or no impact to splicing in MaxEntScan.
The VCEP BP7 rule applies to silent variants with no predicted splice impact. NM_004004.6:c.235del is a coding frameshift producing NP_003995.2:p.(L79Cfs*3), not a silent variant. BP7 is therefore outside its governing scope, regardless of the available SpliceAI max delta score of 0.067.
Silent variant with no predicted impact to splicing. ... No changes. Follow recommendations as outlined in Richard 2015 and/or ClinGen's Sequence Variant Interpretation working group.
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07).
9 paper records listed. 1 cited in the classification.
P.Val37Ile was with a PTC in 92 cases, including 32 with c.235delC (Table 4).
Location Results, Genotype–phenotype correlation; Table 4
Context Multicenter genotype–phenotype cohort of 472 cases with biallelic GJB2 genotypes involving p.Met34Thr or p.Val37Ile; clinical information was incomplete and nonuniform. No c.235delC-specific functional assay was reported.
The gene of the gap junction protein connexin 26 (Cx26) was found to be the main causative gene of autosomal recessive nonsyndromic hearing loss (DFNB1). Although 35delG has been known as the major mutation in Western countries, 235delC was reported to be a specific form of mutation in Asian populations. The objective of the study was to identify how 235delC and E114G changes found in the Korean p
Abstract snippet available in the case literature packet
Connexins are the protein subunits of gap junction channels that allow a direct signaling pathway between networks of cells. The specific role of connexin channels in the homeostasis of different organs has been validated by the association of mutations in several human connexins with a variety of genetic diseases. Several connexins are present in the mammalian cochlea and at least four of them ha
Abstract snippet available in the case literature packet
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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= 0.000191433; MAF= 0.01914%, 309/1614140 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.0066628; MAF= 0.66628%, 299/44876 alleles, homozygotes = 0); grpmax FAF= 0.00604155.
This variant is present in gnomAD v2.1 (AF= 0.000473847; MAF= 0.04738%, 134/282792 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.00651498; MAF= 0.65150%, 130/19954 alleles, homozygotes = 0); grpmax FAF= 0.00643306.
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Pathogenic (36 clinical laboratories) and as pathogenic (1 clinical laboratory) and as Pathogenic by ClinGen Hearing Loss Variant Curation Expert Panel (expert panel). (ClinVarID = 17014)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07).
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV67010611, n = 2 times).
This variant does not lie in a statistically significant hotspot.