rs111033361
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PP3PP1PM2_SupportingPM3_Strong
This summary comes from the ClinGen Evidence Repository: The c.227T>C is a missense variant in GJB2 predicted to cause substitution of leucine to proline at amino acid 76. The highest population minor allele frequency in gnomAD v4.1 is 0.0006779% (8/1180042) in the European (non-Finnish) population, which is a low enough frequency to apply PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_Supporting). The variant has been detected in 4 probands with hearing loss (3.0 PM3 points). For two of those patients, a pathogenic variant was observed in trans (PMID:17666888, 19274344), in a third the variant was observed in a homozygous state (ARUP Laboratories internal data, SCV001158697.1), and in the last patient the variant was observed with another pathogenic variant although with unknown phase (Partners LMM internal data, SCV000061486.5) (PM3_Strong). The variant has been reported to segregate with hearing loss in one affected family member (PP1, PMID:19274344). The REVEL computational prediction tool produced a score of 0.976, which is above the threshold necessary to apply PP3. In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied as specified by the ClinGen Hearing Loss Expert Panel : PM3_Strong, PM2_Supporting, PP1, PP3. (The ClinGen Hearing Loss VCEP Specifications Version 2, 04/17/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA134953/MONDO:0019497/005
Frequency
Consequence
NM_004004.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GJB2 | NM_004004.6 | c.227T>C | p.Leu76Pro | missense_variant | 2/2 | ENST00000382848.5 | |
GJB2 | XM_011535049.3 | c.227T>C | p.Leu76Pro | missense_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GJB2 | ENST00000382848.5 | c.227T>C | p.Leu76Pro | missense_variant | 2/2 | 1 | NM_004004.6 | P1 | |
GJB2 | ENST00000382844.2 | c.227T>C | p.Leu76Pro | missense_variant | 1/1 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152222Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251410Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135900
GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461848Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2AN XY: 727224
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152222Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74364
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 03, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Classified as likely pathogenic by the ClinGen Hearing Loss Expert Panel (ClinVar SCV001428430.1; PMID: 30311386); This variant is associated with the following publications: (PMID: 25388846, 19274344, 30245029, 34599368, 17666888, 22567359, 30311386) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 15, 2023 | For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GJB2 protein function. ClinVar contains an entry for this variant (Variation ID: 44731). This missense change has been observed in individual(s) with non-syndromic deafness (PMID: 19274344). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs111033361, gnomAD 0.004%). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 76 of the GJB2 protein (p.Leu76Pro). - |
not specified Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 01, 2008 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jul 09, 2018 | The GJB2 c.227T>C; p.Leu76Pro variant (rs111033361) has been described in the compound heterozygous state in individuals with hearing loss, ranging from mild to profound (Batissoco 2009, Nogueira 2011, Putcha 2007). It is reported in ClinVar (Variation ID: 44731), and observed in the European (Non-Finnish) population at a low overall frequency of 0.0036% (4/11678 alleles) in the Genome Aggregation Database. The leucine at codon 76 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. Additionally, other variants at positions adjacent to codon 76 (p.Arg75Gln, p.Arg75Trp, p.Trp77Arg) have been described in association with hearing loss and are considered pathogenic (see link to Connexin Deafness database and references therein, Carrasquillo 1997). Based on available information, the p.Leu76Pro variant is considered likely pathogenic. References: Link to Connexin Deafness database: http://davinci.crg.es/deafness/ Batissoco A et al. A novel missense mutation p.L76P in the GJB2 gene causing nonsyndromic recessive deafness in a Brazilian family. Braz J Med Biol Res. 2009 Feb;42(2):168-71. Carrasquillo M et al. Two different connexin 26 mutations in an inbred kindred segregating non-syndromic recessive deafness: implications for genetic studies in isolated populations. Hum Mol Genet. 1997 Nov;6(12):2163-72. Nogueira C et al. Molecular investigation of pediatric portuguese patients with sensorineural hearing loss. Genet Res Int. 2011;2011:587602. Putcha G et al. A multicenter study of the frequency and distribution of GJB2 and GJB6 mutations in a large North American cohort. Genet Med. 2007 Jul;9(7):413-26. - |
Nonsyndromic genetic hearing loss Pathogenic:1
Likely pathogenic, reviewed by expert panel | curation | ClinGen Hearing Loss Variant Curation Expert Panel | Apr 23, 2024 | The c.227T>C is a missense variant in GJB2 predicted to cause substitution of leucine to proline at amino acid 76. The highest population minor allele frequency in gnomAD v4.1 is 0.0006779% (8/1180042) in the European (non-Finnish) population, which is a low enough frequency to apply PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_Supporting). The variant has been detected in 4 probands with hearing loss (3.0 PM3 points). For two of those patients, a pathogenic variant was observed in trans (PMID: 17666888, 19274344), in a third the variant was observed in a homozygous state (ARUP Laboratories internal data, SCV001158697.1), and in the last patient the variant was observed with another pathogenic variant although with unknown phase (Partners LMM internal data, SCV000061486.5) (PM3_Strong). The variant has been reported to segregate with hearing loss in one affected family member (PP1, PMID: 19274344). The REVEL computational prediction tool produced a score of 0.976, which is above the threshold necessary to apply PP3. In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied as specified by the ClinGen Hearing Loss Expert Panel : PM3_Strong, PM2_Supporting, PP1, PP3. (The ClinGen Hearing Loss VCEP Specifications Version 2, 04/17/2024) - |
Autosomal dominant nonsyndromic hearing loss 3A Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | DASA | Feb 14, 2022 | The c.227T>C;p.(Leu76Pro) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 44731; PMID: 19274344; 17666888) - PS4. The variant is present at low allele frequencies population databases (rs111033361 - gnomAD 0.00006569%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Leu76Pro) was detected in trans with a pathogenic variant (PMID: 17666888; 19274344) - PM3. The variant co-segregated with disease in multiple affected family members (PMID: 19274344) - PP1. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is likely pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at