rs80338945
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PP3PP5_Very_Strong
The NM_004004.6(GJB2):c.269T>C(p.Leu90Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000667 in 1,613,914 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: 𝑓 0.00064 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00067 ( 3 hom. )
Consequence
GJB2
NM_004004.6 missense
NM_004004.6 missense
Scores
17
1
1
Clinical Significance
Conservation
PhyloP100: 9.27
Genes affected
GJB2 (HGNC:4284): (gap junction protein beta 2) This gene encodes a member of the gap junction protein family. The gap junctions were first characterized by electron microscopy as regionally specialized structures on plasma membranes of contacting adherent cells. These structures were shown to consist of cell-to-cell channels that facilitate the transfer of ions and small molecules between cells. The gap junction proteins, also known as connexins, purified from fractions of enriched gap junctions from different tissues differ. According to sequence similarities at the nucleotide and amino acid levels, the gap junction proteins are divided into two categories, alpha and beta. Mutations in this gene are responsible for as much as 50% of pre-lingual, recessive deafness. [provided by RefSeq, Oct 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 11 ACMG points.
PM1
In a helix (size 29) in uniprot entity CXB2_HUMAN there are 23 pathogenic changes around while only 1 benign (96%) in NM_004004.6
PP3
MetaRNN computational evidence supports a deleterious effect, 0.834
PP5
Variant 13-20189313-A-G is Pathogenic according to our data. Variant chr13-20189313-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 17016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-20189313-A-G is described in Lovd as [Likely_pathogenic]. Variant chr13-20189313-A-G is described in Lovd as [Pathogenic]. Variant chr13-20189313-A-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| GJB2 | NM_004004.6 | c.269T>C | p.Leu90Pro | missense_variant | 2/2 | ENST00000382848.5 | NP_003995.2 | |
| GJB2 | XM_011535049.3 | c.269T>C | p.Leu90Pro | missense_variant | 2/2 | XP_011533351.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| GJB2 | ENST00000382848.5 | c.269T>C | p.Leu90Pro | missense_variant | 2/2 | 1 | NM_004004.6 | ENSP00000372299 | P1 | |
| GJB2 | ENST00000382844.2 | c.269T>C | p.Leu90Pro | missense_variant | 1/1 | ENSP00000372295 | P1 |
Frequencies
GnomAD3 genomes 0.000638 AC: 97AN: 152150Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000645 AC: 162AN: 251276Hom.: 0 AF XY: 0.000655 AC XY: 89AN XY: 135820
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GnomAD4 genome 0.000638 AC: 97AN: 152150Hom.: 0 Cov.: 33 AF XY: 0.000578 AC XY: 43AN XY: 74332
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:43Uncertain:1Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 1A Pathogenic:13Uncertain:1Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Apr 19, 2019 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2001 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Dec 07, 2019 | NM_004004.5(GJB2):c.269T>C(L90P) is classified as pathogenic in the context of GJB2-related DFNB1 nonsyndromic hearing loss and deafness. Sources cited for classification include the following: PMID 12505163, 10830906, 12189493, 12189487, 15967879, and 21094084. Classification of NM_004004.5(GJB2):c.269T>C(L90P) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Wangler Lab, Baylor College of Medicine | - | This missense GJB2 variant at c.269T>C (p.L90P) was discovered on exome through the Texome Project (R01HG011795). It has been reported in individuals with non-syndromic hearing loss 1A (PMID: 10218527, 12189487, 12497637, 15365987) (PM3), and functional studies suggest this variant is partially defective (PMID: 12189493, 16300957) (PS3). It has been observed in gnomAD with a frequency of 0.060% in the heterozygous state (PM2). This variant is predicted to be deleterious by multiple computational models (CADD: 28.800)(PP3). The evolutionary conservation of this residue is high. We classify this variant as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Integrating Genomics into Medicine, Frazer Institute, University Of Queensland | Jun 02, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Undiagnosed Diseases Network, NIH | Jan 11, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 01, 2017 | Variant summary: The GJB2 c.269T>C (p.Leu90Pro) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant, and this mutation affects a highly conserved residue of the encoded gap junction protein and has been shown to be coupling deficient by in vitro functional assays (Thonnissen_2001). The observed allele frequency in controls, including the large and diverse ExAC cohort, is 108/123096 (1/1140), which is lower than the maximal expected allele frequency for an ARNSHL-causing GJB2 variant (1/40). This variant has been reported in several NSHL patients in homozygous as well as compound heterozygous state with other pathogenic variants, including evidence of cosegregation with disease in multiple families (Rabionet_2000, Marlin_2001, Tang_2006, Salvago_2014). In addition, several diagnostic laboratories/reputable databases classify the variant as pathogenic. Taking all evidence together, this variant has been classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Dec 18, 2013 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Feb 25, 2022 | Criteria applied: PM3_VSTR,PM5_STR,PS3_SUP,PP3; origin unknown but compound heterozygous - |
| Pathogenic, criteria provided, single submitter | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Feb 25, 2016 | The c.269T>C (p.Leu90Pro) missense variant in the GJB2 gene is a common variant reported in individuals affected with autosomal recessive nonsyndromic hearing loss and deafness (Löffler et al., 2001). This variant has been observed in trans with the well-characterized GJB2c.35delG variant (Denoyelle et al., 1999, Löffler et al., 2001). Multiple studies have shown this variant impairs proper assembly and function of the gap junction channel (Thönnissen et al., 2002; D'Andrea et al., 2002; Bruzzone et al., 2003; Palmada et al., 2006). This c.269T>C has been reported at low frequency or absent in three control population databases (Exome Sequencing Project [ESP] = 0.058%, 1000 Genomes = NA, and ExAC = 0.151%). Multiple lines of computational evidence predict a deleterious effect (GERP = 5.33; CADD = 23.5; PolyPhen = 1; SIFT = 0), and multiple reputable diagnostic laboratories report this variant as pathogenic. Therefore, this collective evidence supports the classification of the c.269T>C (p.Leu90Pro) as a recessive pathogenic variant for Nonsyndromic hearing loss and deafness. - |
| not provided, no classification provided | literature only | GeneReviews | - | - - |
| Uncertain significance, flagged submission | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 29, 2024 | - - |
| Pathogenic, criteria provided, single submitter | curation | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Feb 01, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | May 09, 2017 | - - |
not provided Pathogenic:14
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 16, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 10, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Dec 02, 2022 | The GJB2 c.269T>C; p.Leu90Pro variant (rs80338945) is reported in the literature in multiple individuals and families affected with mild to moderate hearing loss (Denoyelle 1999, Janecke 2002, Likar 2018, Mikstiene 2016, Snoeckx 2005). This variant is reported in ClinVar (Variation ID: 17016), and is found predominantly in the non-Finnish European population with an allele frequency of 0.12% (153/129066 alleles) in the Genome Aggregation Database. Additionally, other variants at this codon (c.269T>G; p.Leu90Arg and c.268C>G; p.Leu90Val) have been reported in individuals with mild hearing loss (Lim 2003, Lipan 2011). Functional analyses of the p.Leu90Pro variant protein shows significant loss of junctional conductance (Bruzzone 2003, D'Andrea 2002, Palmada 2006, Thonnissen 2002). Based on available information, this variant is considered to be pathogenic. REFERENCES Bruzzone R et al. Loss-of-function and residual channel activity of connexin26 mutations associated with non-syndromic deafness. FEBS Lett. 2003 533:79-88. PMID: 12505163. D'Andrea P et al. Hearing loss: frequency and functional studies of the most common connexin26 alleles. Biochem Biophys Res Commun. 2002 296:685-691. PMID: 12176036. Denoyelle F et al. Clinical features of the prevalent form of childhood deafness, DFNB1, due to a connexin-26 gene defect: implications for genetic counselling. Lancet. 1999 353:1298-1303. PMID: 10218527. Janecke AR et al. Progressive hearing loss, and recurrent sudden sensorineural hearing loss associated with GJB2 mutations--phenotypic spectrum and frequencies of GJB2 mutations in Austria. Hum Genet. 2002 111:145-153. PMID: 12189487. Likar T et al. Diagnostic outcomes of exome sequencing in patients with syndromic or non-syndromic hearing loss. PLoS One. 2018 13:e0188578. PMID: 29293505. Lim LH et al. Genotypic and phenotypic correlations of DFNB1-related hearing impairment in the Midwestern United States. Arch Otolaryngol Head Neck Surg. 2003 129:836-840. PMID: 12925341. Lipan M et al. Clinical comparison of hearing-impaired patients with DFNB1 against heterozygote carriers of connexin 26 mutations. Laryngoscope. 2011 121:811-814. PMID: 21287563. Mikstiene V et al. The high frequency of GJB2 gene mutation c.313_326del14 suggests its possible origin in ancestors of Lithuanian population. BMC Genet. 2016 17:45. PMID: 26896187. Palmada M et al. Loss of function mutations of the GJB2 gene detected in patients with DFNB1-associated hearing impairment. Neurobiol Dis. 2006 22:112-118. PMID: 16300957. Snoeckx RL et al. GJB2 mutations and degree of hearing loss: a multicenter study. Am J Hum Genet. 2005 77:945-957. PMID: 16380907. Thonnissen E et al. Human connexin26 (GJB2) deafness mutations affect the function of gap junction channels at different levels of protein expression. Hum Genet. 2002 111:190-197. PMID: 12189493. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Dec 29, 2022 | The frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant segregates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. See PMID: 12176036, 16300957, 12505163. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Feb 01, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 90 of the GJB2 protein (p.Leu90Pro). This variant is present in population databases (rs80338945, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with autosomal recessive deafness (PMID: 10218527, 12172392, 12189487, 12497637, 15365987). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17016). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GJB2 function (PMID: 12189493, 16300957). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Mar 14, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2024 | GJB2: PM3:Very Strong, PM2:Supporting, PP3, PS3:Supporting - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 20, 2020 | Reported in the published literature as homozygous or compound heterozygous with another pathogenic variant in individuals with mild to profound autosomal recessive non-syndromic hearing loss (DFNB1) (Denoyelle et al., 1999; Beck et al., 2015; Tekin et al., 2016; Loeffler et al., 2001); This variant seems common among the Italian and Lithuanian populations (D'Andrea et al., 2002; Mikstiene et al., 2016); In vitro electrophysiological and functional studies demonstrate that L90P impedes formation of functional gap junction channels and hemichannels but does not interfere with function of co-expressed wildtype protein, consistent with its autosomal recessive inheritance (D'Andrea et al., 2002; Thonnissen et al., 2002; Palmada et al., 2006); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27177978, 26850479, 27481527, 30609409, 29554876, 31980526, 22975760, 25087612, 10218527, 12189493, 12176036, 12505163, 16300957, 27224056, 26896187, 25214170, 11313763, 12189487, 27153395, 14738110, 25388846, 29293505, 30094485, 30344259, 31160754, 33096615, 31589614, 32860223) - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Jul 04, 2023 | - - |
Autosomal dominant nonsyndromic hearing loss 3A Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 10, 2019 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PM3,PP2,PP3. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Mar 08, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Apr 29, 2022 | - - |
Hearing impairment Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center | Apr 12, 2021 | PS1_Strong, PM2_Moderate, PM3_Supporting, PM5_Moderate, PP3_Supporting - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 08, 2013 | - - |
| Pathogenic, criteria provided, single submitter | research | CSER _CC_NCGL, University of Washington | Dec 01, 2015 | - - |
Hearing loss Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital | Nov 02, 2016 | - - |
Autosomal dominant keratitis-ichthyosis-hearing loss syndrome;C0265964:Mutilating keratoderma;C0266004:Knuckle pads, deafness AND leukonychia syndrome;C1835672:Palmoplantar keratoderma-deafness syndrome;C1865234:Ichthyosis, hystrix-like, with hearing loss;C2673759:Autosomal recessive nonsyndromic hearing loss 1A;C2675750:Autosomal dominant nonsyndromic hearing loss 3A Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Dec 10, 2021 | GJB2 NM_004004.5 exon 2 p.Leu90Pro (c.269T>C): This variant has been reported in the literature in the homozygous or compound heterozygous state in several individuals with nonsyndromic hearing loss (D'Andrea 2002 PMID:12176036, Tekin 2003 PMID:14738110, Zoll 2003 PMID:12497637, Azaiez 2004 PMID:15365987, Mikstiene 2016 PMID:26896187, Likar 2018 PMID:29293505, Prasad 2018 PMID:29554876). This variant is also present in 0.1% (153/129066) of European alleles in the Genome Aggregation Database https://gnomad.broadinstitute.org/variant/13-20763452-A-G). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:17016). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In addition, functional studies have shown a deleterious effect of this variant through impairment of gap junction channel assembly and function (D'Andrea 2002 PMID:12176036, Bruzzone 2003 PMID:12505163, Palmada 2006 PMID:16300957). However, these studies may not accurately represent in vivo biological function. In summary, this variant is classified as pathogenic based on the data above. - |
Nonsyndromic genetic hearing loss Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | INGEBI, INGEBI / CONICET | Aug 31, 2020 | Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the filter allele frequency of c.269T>C, p.Leu90Pro variant in GJB2 gene is 0.1% (153/129066 European non-Finnish alleles with 95% CI) from Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which meets the BS1_Supporting rule. Computational analysis of p.Leu90Pro change predicted a damage impact to the protein (REVELscore:0.981; PP3). This variant has been identified in at least 15 hearing loss individuals in trans with c.35delG variant and in trans with several known pathogenic variants meeting PM3_VerySrong (PMID: 10218527, 10830906, 10982180, 11313763, 11493200, 12176179, 14985372, 15967879, 163800907, 19173109, 24158611). Functional studies in HeLa cells showed that p.Leu90Pro mutant displayed neither very low incidence of dye transfer (LY and DAPI), not tracer (neurobitin) diffusion (PMID: 12176036, 12189493). In addition to this, electrophysiological recordings in Xenopus Laevis oocytes demonstrated that there was not junctional conductance levels detected when p.Leu90Pro mutant was injected (PMID: 12505163). Besides, partial dominant effect on hCX30 was determined but not on CX26; PS3_Moderate. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive non-syndromic hearing loss: BS1_Supporting, PP3, PM3_VeryStrong, PS3_Moderate. - |
GJB2-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 08, 2024 | The GJB2 c.269T>C variant is predicted to result in the amino acid substitution p.Leu90Pro. This variant has been well documented as causative for autosomal recessive nonsyndromic hearing loss and deafness (Denoyelle et al. 1999. PubMed ID: 10218527; D'Andrea et al. 2002. PubMed ID: 12176036; Minárik et al. 2003. PubMed ID: 15113126; Marlin et al. 2005. PubMed ID: 15967879; Mikstiene et al. 2016. PubMed ID: 26896187; Plevova et al. 2018. PubMed ID: 30344259). This variant is classified as pathogenic. - |
Autosomal recessive nonsyndromic hearing loss 1A;C2675235:Autosomal recessive nonsyndromic hearing loss 1B Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
Deafness Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | DASA | Sep 02, 2021 | The missense variant c.269T>C;p.(Leu90Pro) in the GJB2 gene is classified as pathogenic related with DFNB1 nonsyndromic hearing (ClinVar ID: 17016; OMIM: 121011.0016; PMID: 11313763; 26896187; 20301449; 25214170; 24793888; 12176036; 16300957; 24158611; 22281373; 22037723; 33333757; 29293505; 29311818; 25189242) – PS4. This variant is present at very low allele frequencies population databases (rs80338945 - gnomAD; ABraOM) - PM2_ supporting. The p.Leu90Pro was detected in trans with a pathogenic variant (PMID: 25214170; 24793888; 26896187; 24158611; 22281373; 22037723; 29293505; 25189242) - PM3_very strong; and the predictions coincide with pathogenicity – PP3. In summary, the currently available evidence indicates that the variant is pathogenic. - |
Ichthyosis, hystrix-like, with hearing loss Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 01, 2019 | - - |
See cases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University Hospital Muenster | Jul 16, 2018 | ACMG categories: PS3,PM2,PM3,PP3,PP5 - |
Autosomal dominant keratitis-ichthyosis-hearing loss syndrome;C0265964:Mutilating keratoderma;C0266004:Knuckle pads, deafness AND leukonychia syndrome;C1835672:Palmoplantar keratoderma-deafness syndrome;C1844678:X-linked mixed hearing loss with perilymphatic gusher;C1865234:Ichthyosis, hystrix-like, with hearing loss;C2673759:Autosomal recessive nonsyndromic hearing loss 1A;C2675750:Autosomal dominant nonsyndromic hearing loss 3A Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 18, 2017 | - - |
Rare genetic deafness Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 10, 2017 | The p.Leu90Pro variant in GJB2 is a common, well-known pathogenic variant for au tosomal recessive nonsyndromic hearing loss (Cryns 2004). The p.Leu90Pro variant has been identified in 0.12% (151/126606) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs8033894 5). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency for hearing l oss. In summary, this variant meets criteria to be classified as pathogenic for non-syndromic hearing loss in an autosomal recessive manner. ACMG/AMP Criteria a pplied: PM3_VeryStrong; PS3; PP1; PP3. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
.;.;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;M;M
MutationTaster
Benign
A;A
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;.
REVEL
Pathogenic
Sift
Pathogenic
D;D;.
Sift4G
Pathogenic
D;D;.
Polyphen
D;D;D
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at