ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.131G>A (p.Trp44Ter) (rs104894413)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169176 SCV000220409 likely pathogenic Deafness, autosomal recessive 1A 2014-06-12 criteria provided, single submitter literature only
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000517231 SCV000227321 pathogenic not provided 2015-05-20 criteria provided, single submitter clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000169176 SCV000599731 pathogenic Deafness, autosomal recessive 1A 2017-05-09 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515211 SCV000611267 pathogenic Deafness, autosomal recessive 1A; Mutilating keratoderma; Hystrix-like ichthyosis with deafness; Keratitis-ichthyosis-deafness syndrome, autosomal dominant; Palmoplantar keratoderma-deafness syndrome; Knuckle pads, deafness AND leukonychia syndrome; Deafness, autosomal dominant 3a; Deafness, X-linked 2 2017-05-18 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000517231 SCV000613505 pathogenic not provided 2015-07-08 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169176 SCV000698229 pathogenic Deafness, autosomal recessive 1A 2017-08-08 criteria provided, single submitter clinical testing Variant summary: The GJB2 c.131G>A (p.Trp44X) variant results in a premature termination codon, predicted to cause a truncated or absent GJB2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g., c.139G>T [p.Glu47X], c.167delT [p.Leu56fsX26], and c.169C>T [p.Gln57X]). One in silico tool predicts a damaging outcome for this variant. This variant was found in the large control database ExAC and in control cohorts from the literature at a frequency of 0.0000082 (1/121870 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.025). The variant has been identified in numerous patients reported in the literature in compound heterozygosity with known pathogenic GJB2 variants and as a homozygous allele (e.g., Carranza_CG_2015). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic and pathogenic. Taken together, this variant is classified as pathogenic.
Ambry Genetics RCV000624765 SCV000741870 pathogenic Inborn genetic diseases 2016-11-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001282159 SCV000885519 pathogenic none provided 2019-08-29 criteria provided, single submitter clinical testing The GJB2 c.131G>A; p.Trp44Ter variant (rs104894413) is reported in the literature in multiple individuals affected with nonsyndromic sensorineural hearing loss, both in the homozygous state and in individuals with a second pathogenic variant (Tang 2006, Carranza 2016, Snoeckx 2005, Putcha 2007, Lipan 2011, Roux 2004). In a large North American cohort, the p.Trp44Ter variant was determined as the sixth most common variant in individuals with African descent (Putcha 2007), and it was reported as the most common variant observed in unrelated deaf families from Guatemala, consistent with a founder effect in the Mayan population (Carranza 2016). This variant is found on only six chromosomes (6/250896 alleles) in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on these observations, the p.Trp44Ter variant is considered to be pathogenic. References: Carranza et al. A Mayan founder mutation is a common cause of deafness in Guatemala. Clin Genet. 2016 Apr;89(4):461-465. Lipan et al. Clinical comparison of hearing-impaired patients with DFNB1 against heterozygote carriers of connexin 26 mutations. Laryngoscope. 2011 Apr;121(4):811-4. Putcha 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. Roux et al. Molecular epidemiology of DFNB1 deafness in France. BMC Med Genet. 2004 Mar 6;5:5. Snoeckx et al. GJB2 mutations and degree of hearing loss: a multicenter study. Am J Hum Genet. 2005 Dec;77(6):945-57. Tang 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.
GeneDx RCV000517231 SCV000890303 pathogenic not provided 2021-06-02 criteria provided, single submitter clinical testing Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 183 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 11102979, 21131880, 10376574, 17041943, 26553399, 16380907, 12325027, 24774219, 21287563, 24077912, 26582918, 27535533, 26346709)
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000169176 SCV001448943 pathogenic Deafness, autosomal recessive 1A 2019-04-04 criteria provided, single submitter clinical testing
Baylor Genetics RCV000169176 SCV001523111 pathogenic Deafness, autosomal recessive 1A 2019-09-25 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Invitae RCV000517231 SCV001589924 pathogenic not provided 2020-06-19 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the GJB2 gene (p.Trp44*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 183 amino acids of the GJB2 protein. This variant is present in population databases (rs104894413, ExAC 0.009%). This variant has been observed in individual(s) with GJB2-related conditions (PMID: 26346709, 31620164). ClinVar contains an entry for this variant (Variation ID: 188830). This variant disrupts the C-terminus of the GJB2 protein. Other variant(s) that disrupt this region (p.Trp172*) have been determined to be pathogenic (PMID: 23668481, 26399936, 29773520). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000169176 SCV001786660 pathogenic Deafness, autosomal recessive 1A 2020-11-12 criteria provided, single submitter clinical testing The GJB2 c.131G>A (p.Trp44Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. The p.Trp44Ter variant has been reported in a homozygous state in six individuals with hearing loss and is noted to be a founder variant in the Guatemalan population (Carranza et al. 2016). The variant is also found in a compound heterozygous state with other predicted loss of function variants in at least two affected individuals (Tang et al. 2006). This variant is found at a frequency of in the 0.000174 in the Latino population of the Genome Aggregation Database. Based on the collective evidence and application of the ACMG criteria, the p.Trp44Ter variant is classified as pathogenic for autosomal recessive non-syndromic hearing loss.
OMIM RCV000169176 SCV000280012 pathogenic Deafness, autosomal recessive 1A 2016-10-16 no assertion criteria provided literature only
Natera, Inc. RCV000169176 SCV001453354 pathogenic Deafness, autosomal recessive 1A 2020-09-16 no assertion criteria provided clinical testing

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