NM_004004.6:c.101T>C
Variant summary
Our verdict is Pathogenic. Variant got 8 ACMG points: 8P and 0B. PM3PS4PP3PP1
This summary comes from the ClinGen Evidence Repository: The filtering allele frequency (the lower threshold of the 95% CI of 510/25108) of the c.101T>C (p.Met34Thr) variant in the GJB2 gene is 1.46% for European (non-Finnish) genomes in gnomAD. This is a high enough frequency that, in the absence of conflicting data, might warrant a benign classification based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). However, based on the evidence outlined below, the ClinGen Hearing Loss Expert Panel believes that the evidence for the pathogenicity of this variant for nonsyndromic hearing loss outweighs its high allele frequency in population databases. Therefore, the BA1 code will not contribute to the overall classification. The homozygous genotype and compound heterozygous genotype with another variant in GJB2 have shown to be statistically enriched in patients with nonsyndromic sensorineural hearing loss compared to individuals representative of the general population in gnomAD and/or those who underwent carrier screening at Counsyl. (PS4; PMID:31160754). This study also reported the variant in 27 homozygous affected probands, 17 affected probands with the p.Val37Ile variant in trans, 138 affected probands with a variant asserted to be P/LP in ClinVar, and 78 affected probands with a premature GJB2 termination codon in trans (PM3; PMID 31160754). The REVEL computational prediction analysis tool produced a score of 0.702, which is above the threshold necessary to apply PP3. Most dye transfer and electrical coupling assays support that the variant impacts protein function (PMID:16849369, 12189493, 10556284, 16300957, 15033936, 12189493); however, some assays showed partial function (PMID:27884957), and therefore this evidence was not counted. At least 16 segregations of the p.Met34Thr variant in family members have been described (PP1_Strong, PMID:31160754, 10903123). Of note, the severity of hearing loss is known to be mild on average and there have been multiple accounts of incomplete penetrance of the variant in families/individuals with p.Met34Thr in a biallelic genotype. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic genetic hearing lossbased on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PS4, PP1_Strong, PM3, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA172206/MONDO:0019497/005
Frequency
Consequence
NM_004004.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.00942 AC: 1434AN: 152234Hom.: 9 Cov.: 33
GnomAD3 exomes AF: 0.00868 AC: 2176AN: 250736Hom.: 23 AF XY: 0.00852 AC XY: 1155AN XY: 135590
GnomAD4 exome AF: 0.0123 AC: 18002AN: 1461676Hom.: 149 Cov.: 33 AF XY: 0.0119 AC XY: 8668AN XY: 727104
GnomAD4 genome 0.00941 AC: 1433AN: 152352Hom.: 9 Cov.: 33 AF XY: 0.00949 AC XY: 707AN XY: 74496
ClinVar
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 1A Pathogenic:19Uncertain:1Other:1
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PM3_VeryStrong+PP1_Strong+PP3 -
The GJB2 variant (c.101T>C; p.Met34Thr) was identified in several individuals with hearing loss and segregated in families with mild non-syndromic hearing loss (Lopponen et. al 2012; PMID 22668073) with functional studies supporting pathogenicity (Kelsell et al. 1997, PMID 9139825; Martin et al. 1999, PMID 10556284, Lopponen et. al 2012; PMID 22668073 and Shearer et al. 2014, PMID 2562649). However, this variant is quite prevalent in control databases (1049 alleles out of 122876 and 13 homozygotes in ExAC) and could be associated with reduced penetrance. Other clinical laboratories have classified this variant as pathogenic (SCV000061472 and SCV000112260) and variant of uncertain significance (SCV000193154). -
Criteria applied: PS3_MOD,PM3_VSTR,PM5_STR,PP1_VSTR,PP3 -
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This variant was identified in compound heterozygosity with a second variant in GJB2 in a male patient with congenital bilateral moderate hearing loss. -
This variant has required extensive investigation to determine its clinical significance. It does have high minor allele frequency in several populations (including 2.2% in the European Finnish population within ExAC). Conversely, there is significant literature evidence that this variant is pathogenic with a variable hearing phenotype. -
The c.101T>C (p.Met34Thr) missense variant in the GJB2gene has been previously reported in numerous individuals with autosomal recessive Nonsyndromic hearing loss and has been shown to segregate with disease (Houseman et al., 2001; Bicego et al., 2006; Löppönen et al., 2012).This variant has been observed in trans with the well-characterized GJB2 c.35delG variant (Houseman et al., 2001; Bicego et al., 2006; Pollack et al., 2007). Multiple studies have shown this variant impairs proper assembly and function of the gap junction channel (Martin et al., 1999; D'Andrea et al., 2002; Bicego et al., 2006). The c.101T>C variant has been reported at low frequency in the three control population databases (Exome Sequencing Project [ESP], 1000 Genomes, and ExAC ); however, this variant has been observed as homozygous in 13 individuals in ExAC. Multiple lines of computational evidence predict a deleterious effect. In addition, multiple reputable diagnostic laboratories report this variant as pathogenic. Therefore, this collective evidence supports the classification of the c.101T>C (p.Met34Thr) as a recessive Likely Pathogenic variant for Nonsyndromic hearing loss. -
NM_004004.5(GJB2):c.101T>C(M34T) is classified as pathogenic in the context of GJB2-related DFNB1 nonsyndromic hearing loss and deafness and is typically associated with bilateral mild to moderate hearing loss. Sources cited for classification include the following: PMID 10556284, 16849369, 15033936, 9716127, 23826813 and 16380907. Classification of NM_004004.5(GJB2):c.101T>C(M34T) 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. -
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The GJB2 c.101T>C (p.Met34Thr) has been reported in the literature in multiple individuals and families affected with mild to severe hearing loss (Cucci RA et al., PMID: 11216656; Houseman MJ et al., PMID: 11134236; Wilcox SA et al., PMID: 10830906) and is reported in the ClinVar database as a germline pathogenic and likely pathogenic variant by numerous submitters, including ClinGen Hearing Loss Variant Curation Expert panel. The highest population minor allele frequency in the population database genome aggregation database (v.2.1.1) is 1.29% in the European (non-Finnish) population, which is higher than the incidence of hearing loss (Hearing Loss Variant Curation Expert Panel). However, the homozygous genotype and compound heterozygous genotype with another variant in GJB2 is statistically enriched in patients with nonsyndromic sensorineural hearing loss compared to the general population (gnomAD) or carrier screening (Shen J et al., PMID: 31160754). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to GJB2 function. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic with variable expressivity and incomplete penetrance. -
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Across a selection of literature, the GJB2 c.101T>C (p.Met34Thr) missense variant has been identified in at least 119 patients with an autosomal recessive form of nonsyndromic hearing loss. The variant was found in a homozygous state in 35 patients, in a compound heterozygous state in 66 patients (at least 59 of whom had a pathogenic deletion), and in a heterozygous state in 18 patients (Houseman et al, 2001; Feldmann et al. 2004; Snoeckx et al. 2005; Tang et al. 2006; Pollak et al. 2007; Löppönen et al. 2012; Dória et al. 2015; Mikstiene et al. 2016). This variant is generally associated with mild to moderate nonsyndromic hearing loss, and segregation was observed in a three-generation family (Löppönen et al. 2012). The p.Met34Thr variant was detected in 66 of 5380 control chromosomes mainly in a heterozygous state, and also in family members with normal audiograms, including in two with the variant in a homozygous state, in five with the variant in a compound heterozygous state, and in 23 with the variant in a heterozygous state (Feldmann et al. 2004; Löppönen et al. 2012). This conflicting evidence may be due to reduced penetrance, estimated at 10% in one study (Pollak et al. 2007), presence of other modifying factors (Houseman et al, 2001; Bicego et al. 2006), or due to an age-dependent effect (Pollak et al. 2007). Dória et al. (2015) suggest this variant may be a risk factor for nonsyndromic hearing loss. Functional studies suggest this variant affects intercellular channels based on dye transfer assays in transiently transfected HeLa cells (D'Andrea et al. 2002; Bicego et al. 2006), although at least one study did not observe this (Oshima et al. 2003). In addition, electrical conductance was decreased to 11% of wildtype in the presence of the p.Met34Thr variant (Bicego et al. 2006). The p.Met34Thr variant is reported at a frequency of 0.03535 in the Finnish population of the 1000 Genomes Project. Based on the evidence, the p.Met34Thr variant is classified as likely pathogenic for recessive nonsyndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Variant summary: GJB2 c.101T>C (p.Met34Thr) results in a non-conservative amino acid change located in the Connexin, N-terminal (IPR013092) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0068 in 1604678 control chromosomes including 26 homozygotes. This frequency is not significantly higher than expected for a pathogenic variant in GJB2 causing Autosomal Recessive Non-Syndromic Hearing Loss, allowing no conclusion about variant significance. c.101T>C has been well reported in the literature in studies of individuals affected with hearing loss phenotypes (example, Houseman_2001 through Shen_2019). These data indicate that the variant is likely to be associated with disease. Many publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity measured as Cx26 hemichannel activated conductance following depolarization (example, Palmada_2006). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation with conflicting assessments although a majority of these assessments support a pathogenic outcome. Furthermore, the ClinGen Hearing Loss Expert Panel has classified it as Pathogenic for autosomal recessive nonsyndromic hearing loss with variable expressivity and age-dependent penetrance (Shen_2019). Based on the evidence outlined above, the variant was classified as pathogenic. -
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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 biallelic 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) 0200 - Variant is predicted to result in a missense amino acid change from methionine to threonine. (I) 0252 - This variant is homozygous. (I) 0305 - Variant is present in gnomAD (v2) >=0.01 and <0.03 for a recessive condition (2482 heterozygotes, 28 homozygotes). (I) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated first transmembrane domain (PMID: 19941053). (I) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. Comparable variants, p.(Met34Arg), p.(Met34Ile), p.(Met34Leu) and p.(Met34Val), have strong previous evidence for pathogenicity in patients with deafness (Deafness Variation Database, ClinVar, LOVD). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple unrelated individuals with autosomal recessive non-syndromic deafness, with variable expressivity and incomplete penetrance. This variant has been reviewed by an expert panel to be pathogenic (ClinVar, PMID: 31160754). (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
It is observed in the gnomAD v2.1.1 (https://gnomad.broadinstitute.org) dataset (total allele frequency: 0.900% NA). Predicted Consequence/Location: Missense variant Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 12176036). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.70 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.70 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000017000 /PMID: 9139825). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 31160754). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 31160754). The variant has been reported to co-segregate with the disease in at least 5 similarly affected relatives/individuals in the same family or similarly affected unrelated family (PMID: 10903123, 31160754). Different missense changes at the same codon (p.Met34Arg, p.Met34Ile, p.Met34Leu, p.Met34Lys, p.Met34Val) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000044722 /PMID: 11698809, 16380907, 17666888, 19941053, 33443819 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
The GJB2 c.101T>C (p.M34T) variant has been reported as a mild (hypomorphic) variant that leads to mild to moderate hearing loss when found in the homozygous state or in trans with a more severe pathogenic GJB2 variant (PMID: 22668073; 11134236; 20708129; 17935238). -
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not provided Pathogenic:11
The GJB2 p.M34T variant was identified in the literature in multiple individuals with by hearing loss, and is reported as a pathogenic variant for autosomal recessive nonsyndromic hearing loss with variable expressitivity and incomplete penetrance by the ClinGen Hearing Loss Expert Panel (Coco_2013_PMID_24611097; Doria_2015; Shen_2019_PMID_31160754). The variant was also found to segregate with disease in two Portuguese compound heterozygote siblings, although the siblings exhibited different phenotypes as one exhibited profound hearing loss, while the other sibling only had moderate hearing loss (Lameiras_2015_PMID_26117665). The variant was identified in dbSNP (ID: rs35887622) and ClinVar (classified as pathogenic by ClinGen Hearing Loss Variant Curation Expert Panel for Nonsyndromic hearing loss and deafness and 11 laboratories, as likely pathogenic by Knight Diagnostic Laboratories, as uncertain significance by Johns Hopkins and Division of Human Genetics, Children's Hospital of Philadelphia, as likely benign by Prevention Genetics, and as benign by Invitae). The variant was identified in control databases in 2538 of 282130 chromosomes (28 homozygous) at a frequency of 0.008996 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (Finnish) in 510 of 25108 chromosomes (freq: 0.02031), European (non-Finnish) in 1655 of 128490 chromosomes (freq: 0.01288), Other in 65 of 7214 chromosomes (freq: 0.00901), Ashkenazi Jewish in 82 of 10358 chromosomes (freq: 0.007917), Latino in 163 of 35426 chromosomes (freq: 0.004601) and African in 63 of 24968 chromosomes (freq: 0.002523), but was not observed in the East Asian or South Asian populations. The p.M34 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. Functional studies suggest that this variant alters gap junction function in Xenopus oocytes and mammalian cells (White_1998; Skerrett_2004_PMID_ 15033936; Martin_1999_PMID_ 10556284; Thonnissen_2002_PMID_ 12189493; Bicego_2006_PMID_ 16849369; Zonta_2014_PMID_ 24624091; D’Andrea_2002_PMID_ 12176036). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -
The GJB2 pathogenic mild c.101T>C; p.Met34Thr variant (rs35887622) is reported in ClinVar (Variation ID: 17000), and observed in the Genome Aggregation Database with an overall allele frequency of 0.9% (2538/282130 alleles, including 28 homozygotes). This variant has been previously classified as benign based on population frequency data (Shearer 2014), and has been referred to as a variant with reduced penetrance (Feldmann 2004, Griffith 2000, Pollak 2007, Tang 2006). However, homozygosity for this variant has also been reported to co-segregate with mild to high frequency deafness (Hall 2012, Houseman 2001). Additionally, this variant has been to shown to have a variable phenotype within the same family (Lameiras 2015). Taken together, we consider this variant to be mildly pathogenic. References: Feldmann D et al. Clinical evidence of the nonpathogenic nature of the M34T variant in the connexin 26 gene. Eur J Hum Genet. 2004 Apr;12(4):279-84. PMID: 14694360. Griffith AJ et al. Autosomal recessive non-syndromic neurosensory deafness at DFNB1 not associated with the compound-heterozygous GJB2 (connexin 26) genotype M34T/167delT. Am J Hum Genet. 2000 Sep;67(3):745-9. PMID: 10903123. Hall A et al. Prevalence and audiological features in carriers of GJB2 mutations, c.35delG and c.101T>C (p.M34T), in a UK population study. BMJ Open. 2012 Jul 31;2(4). PMID: 22855627. Houseman MJ et al. Genetic analysis of the connexin-26 M34T variant: identification of genotype M34T/M34T segregating with mild-moderate non-syndromic sensorineural hearing loss. J Med Genet. 2001 Jan;38(1):20-5. PMID: 11134236. Lameiras AR et al. The controversial p.Met34Thr variant in GJB2 gene: Two siblings, one genotype, two phenotypes. Int J Pediatr Otorhinolaryngol. 2015 Aug;79(8):1316-9. PMID: 26117665. Pollak et al. M34T and V37I mutations in GJB2 associated hearing impairment: evidence for pathogenicity and reduced penetrance. Am J Med Genet A. 2007; 143A(21): 2534-2543. PMID: 17935238. Shearer AE et al. Utilizing ethnic-specific differences in minor allele frequency to recategorize reported pathogenic deafness variants. Am J Hum Genet. 2014 Oct 2;95(4):445-53. PMID: 25262649. Tang HY et al. DNA sequence analysis of GJB2, encoding connexin 26: observations from a population of hearing impaired cases and variable carrier rates, complex genotypes, and ethnic stratification of alleles among controls. Am J Med Genet A. 2006; 140(22): 2401-2415. PMID: 17041943. -
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Common GJB2 variant among individuals of European background, with a carrier frequency of about 1% in Europeans (PMID: 31160754; gnomAD); Case control studies suggest this variant is associated with hearing loss; homozygous and compound heterozygous genotypes are statistically enriched in individuals with autosomal recessive nonsyndromic hearing loss compared to the general population (PMID: 31160754); Published functional studies demonstrate a dominant-negative effect leading to impaired intercellular coupling (PMID: 9139825, 10556284, 16849369); Classified as pathogenic by the ClinGen Hearing Loss Expert Panel, and noted to show variable expressivity and incomplete penetrance (SCV000927015.1; ClinVar; PMID: 31160754); This variant is associated with the following publications: (PMID: 21465647, 16300957, 12176036, 25262649, 15070423, 14694360, 11216656, 30094485, 30311386, 35054374, 34761457, 34697415, 22668073, 25214170, 10757647, 22975760, 22995991, 10556284, 12189493, 12384501, 20668687, 9716127, 26117665, 26896187, 11134236, 27153395, 17935238, 22567861, 10888284, 17426645, 9600457, 25388846, 22855627, 9139825, 10830906, 30609409, 29773520, 31163360, 30344259, 31827275, 31980526, 30872718, 31160754, 10903123, 23826813, 34426522, 33096615, 16077952, 33297549, 33105617, 34515852, 37838930, 36675424, 37108562, 36515421, 36048236, 16849369, 16380907, 34599368, 20083784) -
This variant is one of the most common variants associated with autosomal recessive nonsyndromic hearing loss and is reported to have milder disease presentation and reduced penetrance in some families (PMID: 11134236, 16380907, 22668073). Therefore, the apparently high frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). Assessment of experimental evidence suggests this variant results in abnormal protein function. Experiments show this variant results in reduced cell to cell transfer of small molecules (PMID: 12176036, 12189493, 16300957, 16849369, 27884957). -
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This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 34 of the GJB2 protein (p.Met34Thr). This variant is present in population databases (rs35887622, gnomAD 2.0%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with autosomal recessive nonsyndromic sensorineural deafness (PMID: 16077952, 22668073, 26117665; internal data). 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 has been reported to show reduced penetrance (PMID: 31160754). ClinVar contains an entry for this variant (Variation ID: 17000). 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%. For these reasons, this variant has been classified as Pathogenic. -
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GJB2: PM3:Very Strong, PM5, PM2: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
GJB2 NM_004004.5 exon 2 p.Met34Thr (c.101T>C): This variant has been reported in the literature in the homozygous or compound heterozygous state in several individuals with mild to severe nonsyndromic hearing loss, as well as in both affected and unaffected relatives, suggesting that this variant may have reduced penetrance or may act as a modifier of disease (Kelsell 1997 PMID:9139825, Houseman 2001 PMID:11134236, D'Andrea 2002 PMID:12176036, Feldmann 2004 PMID:14694360, Bicego 2006 PMID:16849369, Pollak 2007 PMID:17935238, Lopponen 2012 PMID:22668073, Lameiras 2015 PMID:26117665, Mikstiene 2016 PMID:26896187). This variant is also present in 2% (510/25108) of Finnish alleles in the Genome Aggregation Database, including 9 homozygotes (https://gnomad.broadinstitute.org/variant/13-20763620-A-G), which may indicate that it is a common variant or a risk allele in this population. This variant is also present in ClinVar, with classifications ranging from pathogenic to benign (Variation ID:17000). Evolutionary conservation and computational predictive tools for this variant are unclear. In vitro functional studies predict that this variant will lead to abnormal channel function (Martin 1999 PMID:10556284, D'Andrea 2002 PMID:12176036, Bicego 2006 PMID:16849369). However, at least one study did not demonstrate this (Oshima 2003 PMID:12384501). These studies may not accurately represent in vivo biological function. In summary, this variant is classified as pathogenic based on the data above -
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Nonsyndromic genetic hearing loss Pathogenic:2
The filtering allele frequency (the lower threshold of the 95% CI of 510/25108) of the c.101T>C (p.Met34Thr) variant in the GJB2 gene is 1.46% for European (non-Finnish) genomes in gnomAD. This is a high enough frequency that, in the absence of conflicting data, might warrant a benign classification based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). However, based on the evidence outlined below, the ClinGen Hearing Loss Expert Panel believes that the evidence for the pathogenicity of this variant for nonsyndromic hearing loss outweighs its high allele frequency in population databases. Therefore, the BA1 code will not contribute to the overall classification. The homozygous genotype and compound heterozygous genotype with another variant in GJB2 have shown to be statistically enriched in patients with nonsyndromic sensorineural hearing loss compared to individuals representative of the general population in gnomAD and/or those who underwent carrier screening at Counsyl. (PS4; PMID: 31160754). This study also reported the variant in 27 homozygous affected probands, 17 affected probands with the p.Val37Ile variant in trans, 138 affected probands with a variant asserted to be P/LP in ClinVar, and 78 affected probands with a premature GJB2 termination codon in trans (PM3; PMID 31160754). The REVEL computational prediction analysis tool produced a score of 0.702, which is above the threshold necessary to apply PP3. Most dye transfer and electrical coupling assays support that the variant impacts protein function (PMID: 16849369, 12189493, 10556284, 16300957, 15033936, 12189493); however, some assays showed partial function (PMID: 27884957), and therefore this evidence was not counted. At least 16 segregations of the p.Met34Thr variant in family members have been described (PP1_Strong, PMID: 31160754, 10903123). Of note, the severity of hearing loss is known to be mild on average and there have been multiple accounts of incomplete penetrance of the variant in families/individuals with p.Met34Thr in a biallelic genotype. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic genetic hearing lossbased on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PS4, PP1_Strong, PM3, PP3. -
Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: PS4, PP1_Strong, PM3, PP3. -
Autosomal dominant nonsyndromic hearing loss 3A Pathogenic:1Other:1
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Inborn genetic diseases Pathogenic:1
The c.101T>C (p.M34T) alteration is located in exon 2 (coding exon 1) of the GJB2 gene. This alteration results from a T to C substitution at nucleotide position 101, causing the methionine (M) at amino acid position 34 to be replaced by a threonine (T). _x000D_ _x000D_ for autosomal recessive GJB2-related non-syndromic hearing loss; however, its clinical significance for autosomal dominant GJB2-related non-syndromic hearing loss and autosomal dominant GJB2-related non-syndromic hearing loss with ectodermal involvement is uncertain. Based on data from gnomAD, the C allele has an overall frequency of 0.900% (2538/282130) total alleles studied. The highest observed frequency was 2.031% (510/25108) of European (Finnish) alleles. This alteration has been found to be statistically enriched in patients with non-syndromic sensorineural hearing loss and has been reported to be homozygous or compound heterozygous with a second GJB2 disease-causing allele in multiple affected individuals (Shen, 2019). In addition, this alteration has been shown to segregate with disease (Shen, 2019; Griffith, 2000). Both incomplete penetrance and and variable expressivity of hearing loss has been reported in families and individuals with this alteration and a second-disease causing allele. This amino acid position is well conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -
Autosomal recessive nonsyndromic hearing loss 1A;C2675235:Autosomal recessive nonsyndromic hearing loss 1B Pathogenic:1
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GJB2-related disorder Pathogenic:1
The GJB2 c.101T>C variant is predicted to result in the amino acid substitution p.Met34Thr. This variant has been reported to be causative for mild to moderate autosomal recessive hearing loss with reduced penetrance (Wu et al. 2002. PubMed ID: 12172394; Bicego et al. 2006. PubMed ID: 16849369; Pollak et al. 2007. PubMed ID: 17935238; Mikstiene et al. 2016. PubMed ID: 26896187; Lameiras et al. 2015. PubMed ID: 26117665). Three other amino acid substitutions at the same position (Met34Val, Met34Leu and Met34Arg) have also been reported to be causative for hearing loss. The ClinGen Hearing Loss expert panel has classified this variant as pathogenic for autosomal recessive nonsyndromic hearing loss, noting hearing loss is typically mild with incomplete penetrance (https://www.ncbi.nlm.nih.gov/clinvar/variation/17000/; Shen et al. 2019. PubMed ID: 31160754). This variant is interpreted as pathogenic. -
Autosomal dominant keratitis-ichthyosis-hearing loss syndrome Pathogenic:1
This sequence variant is a single nucleotide substitution (T>C) at position 101 of the coding sequence of the GJB2 gene that results in a methionine to threonine amino acid change at residue 34 of the gap junction protein beta 2 protein. This is a previously reported variant (ClinVar 17000) that has been observed homozygous and compound heterozygous state in many individuals affected by nonsyndromic sensorineural hearing loss (PMID: 31160754, 10903123) and has been shown to segregate with hearing loss in multiple families (PMID: 31160754, 10903123). This variant is present in 19435 of 1614028 alleles (1.204%), including 158 homozygotes, in the gnomAD v4.1.0 population dataset. Multiple bioinformatic tools predict that this amino acid change would be damaging, and the Met34 residue at this position is highly conserved across the vertebrate species examined. Several functional studies have demonstrated inhibited assembly of or decreased function of the variant protein (PMID: 10556284, 12189493, 12189493, 15033936, 16300957, 16849369). A hearing loss variant curation expert panel has classified this variant as pathogenic. Based upon the evidence, we consider this variant to be pathogenic. ACMG Criteria: BS3, PM3, PP1, PP3, PS4 -
Nonsyndromic Deafness Pathogenic:1
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See cases Pathogenic:1
ACMG classification criteria: PS3, PS4, PM2, PP3 -
Hearing impairment Pathogenic:1
PS1_Very strong, PS4_Strong, PM5_Moderate -
Rare genetic deafness Pathogenic:1
The p.Met34Thr variant in GJB2 is well-established as a pathogenic variant. This variant, in homozygosity or in combination with another GJB2 variant, is commonly associated with mild to moderate hearing loss (Pollak 2007 PMID: 17935238, Snoeckx 2005 PMID: 16380907, Shen 2019 PMID: 31160754) and in rare cases, p.Met34Thr may even be associated with normal hearing. ACMG/AMP Criteria applied: PS4, PP1_Strong, PM3_VeryStrong. -
Hearing loss Uncertain:1
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Autosomal recessive nonsyndromic hearing loss 1A;C2675750:Autosomal dominant nonsyndromic hearing loss 3A Other:1
Variant interpretted as Pathogenic and reported on 02-12-2019 by GeneDx. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Computational scores
Source:
Splicing
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