rs370696868
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS1PM1PM5PP3_StrongPP5
The NM_004004.6(GJB2):c.187G>T(p.Val63Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,613,378 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V63A) has been classified as Uncertain significance.
Frequency
Consequence
NM_004004.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GJB2 | NM_004004.6 | c.187G>T | p.Val63Leu | missense_variant | 2/2 | ENST00000382848.5 | |
GJB2 | XM_011535049.3 | c.187G>T | p.Val63Leu | missense_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GJB2 | ENST00000382848.5 | c.187G>T | p.Val63Leu | missense_variant | 2/2 | 1 | NM_004004.6 | P1 | |
GJB2 | ENST00000382844.2 | c.187G>T | p.Val63Leu | missense_variant | 1/1 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152198Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251252Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135776
GnomAD4 exome AF: 0.0000281 AC: 41AN: 1461062Hom.: 0 Cov.: 33 AF XY: 0.0000206 AC XY: 15AN XY: 726662
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152316Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74488
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 10, 2023 | This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 63 of the GJB2 protein (p.Val63Leu). This variant is present in population databases (rs370696868, gnomAD 0.02%). This missense change has been observed in individual(s) with GJB2-related conditions (PMID: 12792423, 25266519, 34403091; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 447443). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GJB2 protein function with a positive predictive value of 95%. This variant disrupts the p.Val63 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jul 19, 2023 | The frequency of this variant in the general population is consistent with pathogenicity. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) This variant is statistically significantly enriched in affected patients as compared to ethnically matched controls. Computational tools predict that this variant is damaging. - |
Autosomal recessive nonsyndromic hearing loss 1A Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jul 05, 2017 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Autosomal dominant nonsyndromic hearing loss 3A Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | New York Genome Center | May 08, 2023 | The inherited heterozygous c.187G>T p.(Val63Leu) variant identified in the GJB2 gene has previously been reported as heterozygous in multiple individuals with non‐syndromic hearing loss [PMID: 21557232, 26252218, 26043044, 19366456, 24612839, 25266519, others] and as compound heterozygous in at least two families with recessively inherited hearing loss [PMID: 19707039, 24507663]. This variant has been deposited in ClinVar [ClinVar ID:447443] as Variant of Uncertain Significance (2 submissions) and Likely Pathogenic (1 submission), and was classified as a Variant of Uncertain by a recent study[PMID: 36048236]. In population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), the c.187G>T variant is observed at ~0.0027% minor allele frequency across populations (with 0 homozygotes), including ~0.03% minor allele frequency in East Asian sub-population which is higher than the expected maximum allele frequency for a pathogenic variant in the GJB2-related dominant hearing loss [https://cspec.genome.network/cspec/ui/svi/doc/GN005]. The c.187G>T variant in GJB2is located in exon 2 of this 2-exon gene and is predicted to replace an evolutionarily conserved valine amino acid with leucine at position 63 of the encoded protein.In silico predictions are in favor of damaging effect for p.(Val63Leu) [REVEL = 0.929]; however, there are no functional studies to support or refute these predictions. Due to the lack of compelling evidence for its pathogenicity, this inherited heterozygous c.187G>T p.(Val63Leu) variant identified in GJB2 is classified as a Variant of Uncertain Significance for GJB2-related autosomal dominant hearing loss. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at