ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.571T>C (p.Phe191Leu) (rs397516878)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hearing Loss Variant Curation Expert Panel RCV000037865 SCV000886635 uncertain significance not specified 2018-09-24 reviewed by expert panel curation 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.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000037865 SCV000061527 likely benign not specified 2011-06-29 criteria provided, single submitter clinical testing Phe191Leu in exon 2 of GJB2: This variant is not expected to have clinical signi ficance due to its occurrence at an equal frequency in the general population (H an 2008, Dahl 2006, Dai 2009, Hwa 2003, Ohtsuka 2003, Posukh 2005, Wattanasirich aigoon 2004).
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001283700 SCV000603821 likely pathogenic none provided 2019-08-20 criteria provided, single submitter clinical testing 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.
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery,Institute of Otolaryngology, Chinese PLA General Hospital RCV001002772 SCV000992417 likely benign Deafness, autosomal dominant 3a criteria provided, single submitter case-control
Pars Genome Lab RCV001002772 SCV001761671 likely benign Deafness, autosomal dominant 3a 2021-07-28 criteria provided, single submitter clinical testing
GeneDx RCV001555873 SCV001777361 uncertain significance not provided 2020-10-13 criteria provided, single submitter clinical testing 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); Observed in homozygous state in a patient with mild sloping to severe hearing loss in published literature (Oguchi et al., 2005); 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, which includes protein predictors and evolutionary conservation, supports a deleterious effect; 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: 29871260, 31160754, 31992338, 26252218, 15700112, 21366436, 28786104, 31195736, 26749107, 20497192, 27627659, 12560944, 27247933, 19366456, 27792752, 24158611, 16840571, 25388846, 25808784, 19043807, 22384008, 15790391, 12792423, 12772454, 23967136, 19707039, 23826813, 15479191, 24256046, 30245029)
Counsyl RCV000674539 SCV000799891 uncertain significance Deafness, autosomal recessive 1A 2018-05-09 no assertion criteria provided clinical testing
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000678891 SCV000805084 pathogenic Hearing loss 2012-12-10 no assertion criteria provided clinical testing

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