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

gnomAD frequency: 0.00001  dbSNP: rs104894413

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169176	SCV000220409	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2014-06-12	criteria provided, single submitter	literature only
Eurofins Ntd Llc (ga)	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	Autosomal recessive nonsyndromic hearing loss 1A	2017-05-09	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000515211	SCV000611267	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A; Mutilating keratoderma; Ichthyosis, hystrix-like, with hearing loss; Autosomal dominant keratitis-ichthyosis-hearing loss syndrome; Palmoplantar keratoderma-deafness syndrome; Knuckle pads, deafness AND leukonychia syndrome; Autosomal dominant nonsyndromic hearing loss 3A; X-linked mixed hearing loss with perilymphatic gusher	2017-05-18	criteria provided, single submitter	clinical testing
Athena Diagnostics	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	Autosomal recessive nonsyndromic hearing loss 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	RCV000517231	SCV000885519	pathogenic	not 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	2021-12-07	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); A different nucleotide change (c.132 G>A) leading to the same nonsense variant has been reported as pathogenic in the published literature and at GeneDx in association with autosomal recessive nonsyndromic hearing loss (Green et al., 1999; Roux et al., 2004; Angeli et al., 2008; Mirna et al., 2015); This variant is associated with the following publications: (PMID: 11102979, 21131880, 10376574, 17041943, 26553399, 16380907, 12325027, 24774219, 21287563, 26582918, 26346709, 15070423, 18758381, 24077912, 27535533)
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000169176	SCV001448943	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2019-04-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000169176	SCV001523111	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2019-09-25	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Labcorp Genetics (formerly Invitae), Labcorp	RCV000517231	SCV001589924	pathogenic	not provided	2023-10-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp44*) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 183 amino acid(s) of the GJB2 protein. This variant is present in population databases (rs104894413, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with autosomal recessive GJB2-related conditions (PMID: 26346709, 31620164). ClinVar contains an entry for this variant (Variation ID: 188830). This variant disrupts a region of the GJB2 protein in which other variant(s) (p.Trp172*) have been determined to be pathogenic (PMID: 23668481, 26399936, 29773520). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, Illumina	RCV000169176	SCV001786660	pathogenic	Autosomal recessive nonsyndromic hearing loss 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	Autosomal recessive nonsyndromic hearing loss 1A	2016-10-16	no assertion criteria provided	literature only
Natera, Inc.	RCV000169176	SCV001453354	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004734765	SCV005363351	pathogenic	GJB2-related disorder	2024-06-03	no assertion criteria provided	clinical testing	The GJB2 c.131G>A variant is predicted to result in premature protein termination (p.Trp44*). This variant was reported in patients with nonsyndromic hearing loss and has been described as a founder variant in the Mayan population of Guatemala (Tang et al. 2006. PubMed ID: 17041943; Carranza et al. 2015. PubMed ID: 26346709; Adadey et al. 2019. PubMed ID: 31620164). This variant is reported in 0.017% of alleles in individuals of Latino descent in gnomAD. Nonsense variants in GJB2 are expected to be pathogenic. This variant is interpreted as pathogenic.