ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.647_650del (p.Arg216fs) (rs587783647)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000146027 SCV000193181 pathogenic Hearing impairment 2013-02-08 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000153313 SCV000227312 pathogenic not provided 2015-03-11 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000217521 SCV000271228 likely pathogenic Rare genetic deafness 2015-06-08 criteria provided, single submitter clinical testing The p.Arg216fs variant in GJB2 has been previously reported in one individual wi th hearing loss who was compound heterozygous for a second pathogenic variant in GJB2 (Prasad 2000, variant reported as c.645_648delTAGA). This variant was abse nt from large population studies, though the ability of these studies to accurat ely detect indels may be limited. This variant is predicted to cause a frameshif t, which alters the protein?s amino acid sequence beginning at position 216 and leads to a new termination codon 17 amino acids downstream, thus resulting in a longer protein (the abnormal protein is 5 amino acids longer than the normal pro tein). This variant is expected to disrupt the normal function of the protein; h owever additional data is needed to confirm this. In summary, although additiona l studies are required to fully establish its clinical significance, the p.Arg21 6fs variant is likely pathogenic based on its presence in compound heterozygosit y with a known pathogenic variant in an affected individual and the predicted im pact to the protein.
Counsyl RCV000175766 SCV000487633 likely pathogenic Deafness, autosomal recessive 1A 2016-06-21 criteria provided, single submitter clinical testing
Counsyl RCV000411907 SCV000487634 likely pathogenic Deafness, autosomal dominant 3a 2016-06-21 criteria provided, single submitter clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000175766 SCV000599765 pathogenic Deafness, autosomal recessive 1A 2017-05-09 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000153313 SCV000613522 pathogenic not provided 2015-07-10 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000175766 SCV000698270 pathogenic Deafness, autosomal recessive 1A 2016-09-07 criteria provided, single submitter clinical testing Variant summary: The c.647_650delGATA (p.Arg216Ilefs) variant in GJB2 gene is a frameshift change predicted to cause loss of normal protein function through protein truncation or nonsense-mediated mRNA decay. The variant is present in the large control population dataset of ExAC at a low frequency 0.000026 (3/117776 chrs tested), which does not exceed the maximal expected frequency of a pathogenic allele (0.025) in this gene. The variant of interest has been reported in multiple affected individuals in compound heterozygous state with confirmed dx of NSHL. In addition, multiple reputable databases/clinical laboratories classified this variant as Pathogenic. Taken together, the variant was classified as Pathogenic.
GeneDx RCV000153313 SCV000709969 likely pathogenic not provided 2021-04-01 criteria provided, single submitter clinical testing Frameshift variant predicted to result in protein truncation, as the last 11 amino acids are replaced with 16 different amino acids.; This variant is associated with the following publications: (PMID: 15365987, 17041943, 11102979, 25288386, 31160754, 17666888)
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001001354 SCV001158549 pathogenic not specified 2019-06-23 criteria provided, single submitter clinical testing The GJB2 c.647_650delGATA; p.Arg216fs variant (rs587783647), also known as c.645_648delTAGA, is reported in the literature in the compound heterozygous state in multiple individuals affected with autosomal-recessive nonsyndromic hearing loss (Azaiez 2004, Hernandez-Juarez 2014, Prasad 2000, Putcha 2007, Tang 2006). This variant is reported as pathogenic or likely pathogenic by multiple laboratories in ClinVar (Variation ID: 158609), and is found in the Latino population with an allele frequency of 0.035% (12/34560 alleles) in the Genome Aggregation Database. This variant results in a premature termination codon in the last exon of the GJB2 gene. While this may not lead to nonsense-mediated decay, it is expected to create an altered protein that would include a sequence of 17 amino acid residues not usually present. Furthermore, functional analyses show that small deletions or additions to the C-terminus of the protein affect channel function (Locke 2011). Based on available information, this variant is considered to be pathogenic. References: Azaiez H et al. GJB2: the spectrum of deafness-causing allele variants and their phenotype. Hum Mutat. 2004 Oct;24(4):305-11. Hernandez-Juarez AA et al. GJB2 and GJB6 mutations are an infrequent cause of autosomal-recessive nonsyndromic hearing loss in residents of Mexico. Int J Pediatr Otorhinolaryngol. 2014 Dec;78(12):2107-12. Locke D et al. Mechanism for modulation of gating of connexin26-containing channels by taurine. J Gen Physiol. 2011 Sep;138(3):321-39. Prasad S et al. Genetic testing for hereditary hearing loss: connexin 26 (GJB2) allele variants and two novel deafness-causing mutations (R32C and 645-648delTAGA). Hum Mutat. 2000 Dec;16(6):502-8. Putcha GV et al. A multicenter study of the frequency and distribution of GJB2 and GJB6 mutations in a large North American cohort. Genet Med. 2007 Jul;9(7):413-26. 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 Nov 15;140(22):2401-15.
Invitae RCV000153313 SCV001206581 pathogenic not provided 2020-09-02 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the GJB2 gene (p.Arg216Ilefs*17). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 11 amino acids of the GJB2 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in individual(s) with sensorineural hearing loss (PMID: 11102979, 17041943, 25288386, 17666888). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.645-648delTAGA in the literature. ClinVar contains an entry for this variant (Variation ID: 158609). Experimental studies and prediction algorithms are not available or were not evaluated for this variant, and the functional significance of the affected amino acid(s) is currently unknown. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV001266307 SCV001444480 likely pathogenic Inborn genetic diseases 2018-08-23 criteria provided, single submitter clinical testing

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