rs80338945

Variant names:

• chr13-20189313-A-G
• rs80338945
• NM_004004.6:c.269T>C

Your query was ambiguous. Multiple possible variants found:

• chr13-20189313-A-G
• chr13-20189313-A-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PP3 PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:46 U:1 O:1
• 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]

ACMG classification

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 rank	MANE	Protein	UniProt
GJB2	NM_004004.6	c.269T>C	p.Leu90Pro	missense_variant	Exon 2 of 2	ENST00000382848.5	NP_003995.2
GJB2	XM_011535049.3	c.269T>C	p.Leu90Pro	missense_variant	Exon 2 of 2		XP_011533351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJB2	ENST00000382848.5	c.269T>C	p.Leu90Pro	missense_variant	Exon 2 of 2	1	NM_004004.6	ENSP00000372299.4
GJB2	ENST00000382844.2	c.269T>C	p.Leu90Pro	missense_variant	Exon 1 of 1	6		ENSP00000372295.1

Frequencies

GnomAD3 genomes AF: 0.000638 AC: 97 AN: 152150 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00116

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000645 AC: 162 AN: 251276 Hom.: 0 AF XY: 0.000655 AC XY: 89 AN XY: 135820

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.000232

Gnomad NFE exome AF: 0.00123

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000670 AC: 979 AN: 1461764 Hom.: 3 Cov.: 33 AF XY: 0.000674 AC XY: 490 AN XY: 727190

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000425

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000319

Gnomad4 NFE exome AF: 0.000796

Gnomad4 OTH exome AF: 0.000778

GnomAD4 genome AF: 0.000638 AC: 97 AN: 152150 Hom.: 0 Cov.: 33 AF XY: 0.000578 AC XY: 43 AN XY: 74332

Gnomad4 AFR AF: 0.0000966

Gnomad4 AMR AF: 0.000786

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00116

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000765 Hom.: 0

Bravo AF: 0.000582

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000881 AC: 107

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:46 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 1A Pathogenic:14 Uncertain:1 Other:1

Feb 25, 2022

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PM3_VSTR,PM5_STR,PS3_SUP,PP3; origin unknown but compound heterozygous -

Dec 18, 2013

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 09, 2017

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 19, 2019

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 02, 2023

Integrating Genomics into Medicine, Frazer Institute, University Of Queensland

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 25, 2016

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Feb 01, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Sep 01, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 16, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with both deafness and skin conditions (OMIM). Dominant negative is also a suggested mechanism (PMID: 28428247). (I) 0108 - This gene is associated with both recessive and dominant disease. The autosomal dominant diseases are commonly associated with pathogenic missense variants. The autosomal recessive disease is associated with bi-allelic loss-of-function variants and includes missense and protein truncating variants (NIH Genetics Home Reference, PMID: 12792423). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID:31160754). (I) 0115 - Variants in this gene are known to have variable expressivity. Severity can range from mild to profound with intrafamilial variability also commonly seen. Commonly, truncating variants are associated to a more severe hearing loss (PMID: 20301449). (I) 0200 - Variant is predicted to result in a missense amino acid change from leucine to proline. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (178 heterozygotes, 0 homozygote). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and very highly conserved with a moderate amino acid change. 0600 - Variant is located in the annotated Connexin domain (DECIPHER). (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. This variant is a well-reported pathogenic variant, primarily associated with autosomal recessive hearing loss (ClinVar, PMID: 20301449). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Dec 07, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 29, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Jan 11, 2019

Undiagnosed Diseases Network, NIH

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Wangler Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Pathogenic:14

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GJB2: PM3:Very Strong, PM2:Supporting, PP3, PS3:Supporting -

Jan 20, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Dec 02, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 14, 2018

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 01, 2021

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 14, 2024

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. (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. -

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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -

Jul 04, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 16, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 10, 2014

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal dominant nonsyndromic hearing loss 3A Pathogenic:3

Jan 10, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PM3,PP2,PP3. -

Apr 29, 2022

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 08, 2016

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hearing impairment Pathogenic:3

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 01, 2015

CSER _CC_NCGL, University of Washington

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Apr 12, 2021

Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS1_Strong, PM2_Moderate, PM3_Supporting, PM5_Moderate, PP3_Supporting -

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:2

Apr 22, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 10, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

GJB2-related disorder Pathogenic:2

Oct 30, 2023

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.269T>C (p.Leu90Pro) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. This is a known Pathogenic variant that has been previously reported as a compound heterozygous change in patients with autosomal recessive nonsyndromic hearing loss (PMID: 10218527, 11313763, 12172392, 12189487, 14738110, 15365987, 16380907). Different amino acid changes at the same residue (p.Leu90Arg and p.Leu90Val) have been previously reported in individuals with hearing loss (PMID: 21287563, 12925341). Multiple functional studies have shown that the c.269T>C (p.Leu90Pro) variant impairs proper assembly and function of the gap junction channels (PMID: 12176036, 12189493, 12505163, 15033936, 16300957). The c.269T>C (p.Leu90Pro) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.06% (178/282666), and is absent in the homozygous state. Based on the available evidence, c.269T>C (p.Leu90Pro) is classified as Pathogenic. -

Aug 08, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Hearing loss Pathogenic:1

Nov 02, 2016

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nonsyndromic genetic hearing loss Pathogenic:1

Aug 31, 2020

INGEBI, INGEBI / CONICET

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Autosomal recessive nonsyndromic hearing loss 1A;C2675235:Autosomal recessive nonsyndromic hearing loss 1B Pathogenic:1

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Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Deafness Pathogenic:1

Sep 02, 2021

DASA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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See cases Pathogenic:1

Jul 16, 2018

Institute of Human Genetics, University Hospital Muenster

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

May 18, 2017

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Rare genetic deafness Pathogenic:1

Aug 10, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D;D;D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	.;.;D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.83	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.3	M;M;M
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.6	D;D;.
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0010	D;D;.
Polyphen		1.0	D;D;D
Vest4		0.99
MVP		0.96
MPC		0.34
ClinPred		0.21	T
GERP RS		5.3
Varity_R		0.99
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs80338945; hg19: chr13-20763452;