ClinVar Miner

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

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000037865 SCV000603821 likely pathogenic not specified 2016-10-17 criteria provided, single submitter clinical testing
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.
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000678891 SCV000805084 pathogenic Hearing loss 2012-12-10 no assertion criteria provided clinical testing
Counsyl RCV000674539 SCV000799891 uncertain significance Deafness, autosomal recessive 1A 2018-05-09 criteria provided, single submitter clinical testing
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).

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