rs111033190
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong
The ENST00000382848.5(GJB2):c.95G>T(p.Arg32Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,613,756 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R32C) has been classified as Pathogenic.
Frequency
Consequence
ENST00000382848.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GJB2 | NM_004004.6 | c.95G>T | p.Arg32Leu | missense_variant | 2/2 | ENST00000382848.5 | NP_003995.2 | |
GJB2 | XM_011535049.3 | c.95G>T | p.Arg32Leu | missense_variant | 2/2 | XP_011533351.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GJB2 | ENST00000382848.5 | c.95G>T | p.Arg32Leu | missense_variant | 2/2 | 1 | NM_004004.6 | ENSP00000372299 | P1 | |
GJB2 | ENST00000382844.2 | c.95G>T | p.Arg32Leu | missense_variant | 1/1 | ENSP00000372295 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152126Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000319 AC: 8AN: 250526Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135484
GnomAD4 exome AF: 0.0000116 AC: 17AN: 1461630Hom.: 0 Cov.: 33 AF XY: 0.0000138 AC XY: 10AN XY: 727078
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152126Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74306
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 07, 2024 | This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 32 of the GJB2 protein (p.Arg32Leu). This variant is present in population databases (rs111033190, gnomAD 0.02%). This missense change has been observed in individuals with autosomal recessive non-syndromic deafness (PMID: 19157576, 20154630, 22925408). ClinVar contains an entry for this variant (Variation ID: 499513). 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.Arg32 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been observed in individuals with GJB2-related conditions (PMID: 11493200), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 06, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 03, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in patients with hearing loss in published literature (PMID: 12172394, 19157576, 25085072); This variant is associated with the following publications: (PMID: 25388846, 21112098, 24840842, 26186295, 29542069, 20154630, 22925408, 25085072, 19157576, 12172394) - |
Nonsyndromic genetic hearing loss Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 21, 2022 | Variant summary: GJB2 c.95G>T (p.Arg32Leu) results in a non-conservative amino acid change located in the first transmembrane domain (Joseph_2009) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 250526 control chromosomes. c.95G>T has been reported in the literature as homozygous and compound heterozygous genotypes in individuals affected with Non-Syndromic Hearing Loss (example, Wu_2002, Yamuna Joseph_2009, Chan_2010, de la Luz Arenas-Sordo_2012). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals | May 11, 2022 | - - |
Hearing loss Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital | Apr 22, 2014 | - - |
Autosomal recessive nonsyndromic hearing loss 1A Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Mar 06, 2017 | - - |
Autosomal dominant keratitis-ichthyosis-hearing loss syndrome;C0265964:Mutilating keratoderma;C0266004:Knuckle pads, deafness AND leukonychia syndrome;C1835672:Palmoplantar keratoderma-deafness syndrome;C1844678:X-linked mixed hearing loss with perilymphatic gusher;C1865234:Ichthyosis, hystrix-like, with hearing loss;C2673759:Autosomal recessive nonsyndromic hearing loss 1A;C2675750:Autosomal dominant nonsyndromic hearing loss 3A Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 06, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at