rs397516878
Variant summary
Our verdict is Uncertain significance. Variant got -2 ACMG points: 3P and 5B. PS3_SupportingPP3BS2BS1_SupportingPM3_Supporting
This summary comes from the ClinGen Evidence Repository: The c.571T>C (p.Phe191Leu) variant in GJB2 has been reported in over 19 Asian probands in the literature. However, a case control comparison using Chi-squared analysis did not show a statistical significance between cases and controls in the published studies, or between cases and East Asians in gnomAD (case chromosomes= 19/16415, control chromosomes = 6/8626, 36/18870 East Asian chromosomes in gnomAD; PMIDs 19366456, 15700112, 23826813, 27247933, 27792752, 12792423, 12560944, 19043807, 27627659, 20497192 and https://doi.org/10.1016/S1672-2930(07)50004-8). The filtering allele frequency of the p.Phe191Leu variant in the GJB2 gene is 0.14% for East Asian chromosomes in gnomAD (36/18870 with 95% CI), which is a higher frequency than would be expected for an autosomal recessive pathogenic variant based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (BS1_Supporting). This variant has been detected in 1 individual with hearing loss who was homozygous for the variant, and in 4 compound heterozygous individuals who had a second pathogenic GJB2 variant identified (3 with p.Val37Ile and 1 with c.235delC) (Oguchi 2005 PMID:15700112; ARUP SCV000603821; Partners Lab for Molecular Medicine SCV000061527). Phase was not confirmed for any of these individuals. It is possible that these homozygous and compound heterozygous observations are due to the relatively high allele frequencies of these variants in gnomAD and therefore PM3 was downgraded (PM3_Supporting). In addition, this variant was reported in the homozygous state in a normal hearing parent (BS2, Wattanasirichiagoon 2004, PMID 15479191). Computational prediction analysis using REVEL suggests that the variant may impact the protein (PP3). Two in vitro functional studies demonstrates that this variant resulted in abnormal protein trafficking and retention of the protein in the endoplasmic reticulum; however, further electrical coupling studies were not performed (PS3_Supporting; PMID:23967136, 26749107). In summary, due to conflicting evidence, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1_Supporting, BS2, PM3_Supporting, PS3_Supporting, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA134989/MONDO:0019497/005
Frequency
Consequence
NM_004004.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GJB2 | NM_004004.6 | c.571T>C | p.Phe191Leu | missense_variant | 2/2 | ENST00000382848.5 | |
GJB2 | XM_011535049.3 | c.571T>C | p.Phe191Leu | missense_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GJB2 | ENST00000382848.5 | c.571T>C | p.Phe191Leu | missense_variant | 2/2 | 1 | NM_004004.6 | P1 | |
GJB2 | ENST00000382844.2 | c.571T>C | p.Phe191Leu | missense_variant | 1/1 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152192Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000143 AC: 36AN: 251376Hom.: 0 AF XY: 0.000103 AC XY: 14AN XY: 135878
GnomAD4 exome AF: 0.0000260 AC: 38AN: 1461602Hom.: 0 Cov.: 32 AF XY: 0.0000234 AC XY: 17AN XY: 727102
GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152310Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74482
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 22, 2023 | Observed frequently in unrelated patients of Asian ancestry with sensorineural hearing loss, often in the heterozygous state with no second GJB2 variant identified (Hwa et al., 2003; Chen et al., 2009; Wei et al., 2013; Luo et al., 2017); Reported in published literature in the homozygous state in a patient with mild sloping to severe hearing loss, and in the homozygous state in a clinically unaffected adult (Wattanasirichaigoon et al., 2004; Oguchi et al., 2005); Observed in a patient with bilateral profound sensorineural hearing loss who also harbored a de novo insertion/deletion variant involving the EYA1 gene (Zheng et al., 2021); Published functional studies demonstrate a damaging effect due to mislocalization of the protein, however, electrical coupling studies were not performed (Kim et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Classified as a variant of uncertain significance by the ClinGen Hearing Loss Expert Panel (SCV000886635.1; Oza et al., 2018); This variant is associated with the following publications: (PMID: 12772454, 22384008, 24158611, 30245029, 12560944, 19366456, 20497192, 24256046, 23967136, 12792423, 15790391, 19043807, 25808784, 25388846, 16840571, 27792752, 27627659, 27247933, 31195736, 21366436, 26252218, 31992338, 31160754, 29871260, 15700112, 15479191, 19707039, 23826813, 28786104, 34403091, 33880118, 26749107, 31581539, 35212567, 37373495) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | May 17, 2023 | Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 23967136, 26749107) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 03, 2022 | The p.Phe191Leu variant in GJB2 has been reported in >20 individuals with hearing loss in either the heterozygous, compound heterozygous or homozygous state (Hwa 2003 PMID: 12792423, Ohtsuka 2003 PMID: 12560944, Wattanasirichaigoon 2004 PMID: 15479191, Dai 2009 PMID: 19366456, Wei 2013 PMID: 23826813, Liu 2015 PMID: 25808784, Gao 2016 PMID: 27792752). However it has also been found in one individual without hearing loss in the homozygous state (Wattanasirichaigoon 2004 PMID: 15479191). It has also been identified in 0.19% (37/19954) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant was classified as Uncertain Significance on Sep 24, 2018 by the ClinGen-approved Hearing Loss Variant Curation expert panel (Variation ID 44760). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies provide some evidence that this variant impacts the ability of the protein to leave the cell (Ambrosi 2013 PMID: 2396713 6, Kim 2016 PMID: 26749107); however, these types of assays may not accurately represent biological function. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM3_M, PP3, PS3_S, BS1, BS2. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 20, 2019 | The GJB2 c.571T>C; p.Phe191Leu variant (rs397516878) is reported in the literature in individuals affected with hearing loss but also in normal hearing controls (Dahl 2006, Hwa 2003, Oguchi 2005, Ohtsuka 2003, Posukh 2019, Shi 2016, Wattanasirichaigoon 2004, Wei 2013). This variant has been observed in the compound heterozygous state in affected individuals tested at ARUP Laboratories and has been reported in the homozygous state in a mildly affected individual (Oguchi 2005), but it is also reported in a homozygous individual with normal hearing (Wattanasirichaigoon 2005). This variant is found in the East Asian population with an overall allele frequency of 0.19% (37/19954 alleles) in the Genome Aggregation Database. The phenylalanine at codon 191 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Indeed, functional studies suggest the variant protein is mislocalized in cultured cells (Ambrosi 2013); however, its ability to form functional gap junctions has not been adequately tested. Due to limited and conflicting information, the clinical significance of the p.Phe191Leu variant is uncertain at this time. References: Ambrosi C et al. Analysis of trafficking, stability and function of human connexin 26 gap junction channels with deafness-causing mutations in the fourth transmembrane helix. PLoS One. 2013; 8(8):e70916. Dahl HH et al. The contribution of GJB2 mutations to slight or mild hearing loss in Australian elementary school children. J Med Genet. 2006;43(11):850-855. Hwa HL et al. Mutation spectrum of the connexin 26 (GJB2) gene in Taiwanese patients with prelingual deafness. Genet Med. 2003;5(3):161-165. Oguchi T et al. Clinical features of patients with GJB2 (connexin 26) mutations: severity of hearing loss is correlated with genotypes and protein expression patterns. J Hum Genet. 2005;50(2):76-83. Ohtsuka A et al. GJB2 deafness gene shows a specific spectrum of mutations in Japan, including a frequent founder mutation. Hum Genet. 2003;112(4):329-333. Posukh OL et al. Unique Mutational Spectrum of the GJB2 Gene and its Pathogenic Contribution to Deafness in Tuvinians (Southern Siberia, Russia): A High Prevalence of Rare Variant c.516G>C (p.Trp172Cys). Genes (Basel). 2019;10(6):429. Shi L et al. Prevalence of GJB2 gene mutation in 330 cochlear implant patients in the Jiangsu province. J Laryngol Otol. 2016;130(10):902-906. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 02, 2021 | This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 191 of the GJB2 protein (p.Phe191Leu). This variant is present in population databases (rs397516878, gnomAD 0.2%). This missense change has been observed in individual(s) with hearing loss (PMID: 12560944, 12792423, 15479191, 15790391, 26252218). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 44760). 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. Experimental studies have shown that this missense change affects GJB2 function (PMID: 23967136, 26749107). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 16, 2024 | Variant summary: GJB2 c.571T>C (p.Phe191Leu) results in a non-conservative amino acid change located in the gap junction protein, cysteine-rich domain (IPR019570) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3e-05 in 1617728 control chromosomes, predominantly at a frequency of 0.00096 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 3-fold of the estimated maximal expected allele frequency for a pathogenic variant in GJB2 causing Non-Syndromic Hearing Loss phenotype (0.00034), suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.571T>C has been reported in the literature in the heterozygous state in multiple individuals of East Asian ancestry affected with Non-Syndromic Hearing Loss where no second variant has been reported, or a second variant was found that has been classified as benign (e.g. Ohtsuka_2003, Hwa_2003, Wattanasirichaigoon_2004, Ming-kun_2007, Dai_2009, Shin_2012, Wei_2013, Du_2014 Jiang_2015, Yu_2020). It has also been reported as a compound heterozygous genotype in several affected individuals, including at least one case where it was found in trans with a pathogenic variant (e.g. Jiang_2015, Yu_2020), and in a homozygous patient with a mild phenotype (Oguchi_2005). However, the variant has also been reported in the heterozygous state in healthy control individuals (e.g. Ohtsuka_2003, Hwa_2003, Posukh_2005, Nishio_2015) and in the homozygous state in an unaffected individual who was the parent of a heterozygous proband (Wattanasirichaigoon_2004). These reports do not allow for any conclusion about association of the variant with Non-Syndromic Hearing Loss. At least two publications report experimental evidence evaluating an impact on protein function in vitro and found that the variant showed improper protein trafficking with localization in the cytoplasm, particularly within the ER; however, its ability to form functional gap junctions was not assessed further (Ambrosi_2013, Kim_2016). The following publications have been ascertained in the context of this evaluation (PMID: 23967136, 19366456, 25149764, 12792423, 26252218, 26749107, 25788563, 15700112, 12560944, 15790391, 22701767, 15479191, 23826813, 31992338, https://doi.org/10.1016/S1672-2930(07)50004-8). ClinVar contains an entry for this variant (Variation ID: 44760). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Uncertain significance, reviewed by expert panel | curation | ClinGen Hearing Loss Variant Curation Expert Panel | Sep 24, 2018 | The c.571T>C (p.Phe191Leu) variant in GJB2 has been reported in over 19 Asian probands in the literature. However, a case control comparison using Chi-squared analysis did not show a statistical significance between cases and controls in the published studies, or between cases and East Asians in gnomAD (case chromosomes= 19/16415, control chromosomes = 6/8626, 36/18870 East Asian chromosomes in gnomAD; PMIDs 19366456, 15700112, 23826813, 27247933, 27792752, 12792423, 12560944, 19043807, 27627659, 20497192 and https://doi.org/10.1016/S1672-2930(07)50004-8). The filtering allele frequency of the p.Phe191Leu variant in the GJB2 gene is 0.14% for East Asian chromosomes in gnomAD (36/18870 with 95% CI), which is a higher frequency than would be expected for an autosomal recessive pathogenic variant based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (BS1_Supporting). This variant has been detected in 1 individual with hearing loss who was homozygous for the variant, and in 4 compound heterozygous individuals who had a second pathogenic GJB2 variant identified (3 with p.Val37Ile and 1 with c.235delC) (Oguchi 2005 PMID: 15700112; ARUP SCV000603821; Partners Lab for Molecular Medicine SCV000061527). Phase was not confirmed for any of these individuals. It is possible that these homozygous and compound heterozygous observations are due to the relatively high allele frequencies of these variants in gnomAD and therefore PM3 was downgraded (PM3_Supporting). In addition, this variant was reported in the homozygous state in a normal hearing parent (BS2, Wattanasirichiagoon 2004, PMID 15479191). Computational prediction analysis using REVEL suggests that the variant may impact the protein (PP3). Two in vitro functional studies demonstrates that this variant resulted in abnormal protein trafficking and retention of the protein in the endoplasmic reticulum; however, further electrical coupling studies were not performed (PS3_Supporting; PMID: 23967136, 26749107). In summary, due to conflicting evidence, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1_Supporting, BS2, PM3_Supporting, PS3_Supporting, PP3. - |
Autosomal recessive nonsyndromic hearing loss 1A Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Counsyl | May 09, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Integrating Genomics into Medicine, Frazer Institute, University Of Queensland | Jun 02, 2023 | - - |
Autosomal dominant nonsyndromic hearing loss 3A Benign:2
Likely benign, criteria provided, single submitter | case-control | Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Pars Genome Lab | Jul 28, 2021 | - - |
Hearing loss Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital | Dec 10, 2012 | - - |
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 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 06, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at