13-20189332-C-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_004004.6(GJB2):c.250G>A(p.Val84Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V84L) has been classified as Likely pathogenic.
Frequency
Consequence
NM_004004.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251338Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135856
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461806Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 727212
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 1A Pathogenic:4
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not provided Pathogenic:3
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with hearing loss. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 17660464) In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. -
Published functional studies demonstrate a damaging effect with the variant resulting in gap junctions that are incapable of intercellular coupling (Matos et al., 2007); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19101659, 25266519, 12865758, 25388846, 16222667, 24774219, 23668481, 9529365, 31160754, 30344259, 34440441, 34652575, 36100214, 26553399, 17660464, 31992338, 32067424) -
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 84 of the GJB2 protein (p.Val84Met). This variant is present in population databases (rs104894409, gnomAD 0.01%). This missense change has been observed in individuals with autosomal recessive non-syndromic deafness (PMID: 30344259, 31160754). ClinVar contains an entry for this variant (Variation ID: 17036). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GJB2 protein function with a positive predictive value of 95%. This variant disrupts the p.Val84 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11556849, 12172394, 16380907, 19235794). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Progressive sensorineural hearing impairment Pathogenic:1
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Autosomal dominant nonsyndromic hearing loss 3A Pathogenic:1
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Rare genetic deafness Pathogenic:1
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GJB2-related disorder Pathogenic:1
The GJB2 c.250G>A variant is predicted to result in the amino acid substitution p.Val84Met. This variant has been reported in the homozygous and compound heterozygous states in patients with nonsyndromic hearing loss (Plevova. 2018. PubMed ID: 30344259; Pandya. 2020. PubMed ID: 32067424; Table S2, Shen. 2019. PubMed ID: 31160754; Zhang. 2011. PubMed ID: 21366436; Cheng. 2005. PubMed ID: 16222667; Martínez-Saucedo. 2015. PubMed ID: 26553399; Primignani. 2009. PubMed ID: 19371219; Loeza-Becerra. 2014. PubMed ID: 24774219). This variant is reported in 0.0099% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-20763471-C-T). This variant is interpreted as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at