ClinVar Genomic variation as it relates to human health

The GJB2 c.647_650delGATA; p.Arg216IlefsTer17 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.

This sequence change creates a premature translational stop signal (p.Arg216Ilefs*17) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 11 amino acid(s) of the GJB2 protein. This variant is present in population databases (rs587783647, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with autosomal recessive sensorineural deafness (PMID: 11102979, 17041943, 17666888, 25288386). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.645-648delTAGA. ClinVar contains an entry for this variant (Variation ID: 158609). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic.

The p.Arg216fs variant in GJB2 has been previously reported in at least 8 individuals with hearing loss, at least 4 of which were compound heterozygous for a second pathogenic variant in GJB2 (Prasad 2000 PMID: 11102979, Tang 2006 PMID: 17041943, Putcha 2007 PMID: 17666888, Hernandez-Juarez 2014 PMID: 25288386). This variant has also been reported as c.645_648delTAGA in the literature. It has also been identified in 0.03% (12/34560) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 158609). This variant is predicted to cause a frameshift, 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 protein). This variant is expected to disrupt the normal function of the protein; however additional data is needed to confirm this. In summary, the p.Arg216fs variant is pathogenic for autosomal recessive nonsyndromic hearing loss. ACMG/AMP Criteria applied: PM3_Very Strong, PM4, PM2_Supporting.

Frameshift variant predicted to result in protein elongation, 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)

Variant summary: GJB2 c.647_650delGATA (p.Arg216IlefsX17) causes a frameshift which results in an extension of the protein. The variant allele was found at a frequency of 4.8e-05 in 250054 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in GJB2 causing Autosomal Recessive Non-Syndromic Hearing Loss (4.8e-05 vs 0.025), allowing no conclusion about variant significance. c.647_650delGATA has been reported in the literature in multiple individuals affected with Autosomal Recessive Non-Syndromic Hearing Loss (examples: Prasad_2000, Tang_2006, Putcha_2007). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 11102979, 17666888, 17041943). ClinVar contains an entry for this variant (Variation ID: 158609). Based on the evidence outlined above, the variant was classified as pathogenic.

The GJB2 c.647_650delGATA variant is predicted to result in a frameshift and premature protein termination (p.Arg216Ilefs*17). This variant has been reported as causative for autosomal recessive deafness (also described as c.645_648delGATA; Prasad et al 2000. PubMed ID: 11102979; Azaiez et al 2004. PubMed ID: 15365987; Putcha et al 2007. PubMed ID: 17666888). This variant is reported in 0.035% of alleles in individuals of Latino descent in gnomAD. Frameshift variants in GJB2 are expected to be pathogenic. This variant is interpreted as pathogenic.