rs1131691322
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong
The ENST00000361726.7(GJB1):āc.307A>Gā(p.Lys103Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000917 in 1,090,022 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā ā ). Synonymous variant affecting the same amino acid position (i.e. K103K) has been classified as Likely benign.
Frequency
Consequence
ENST00000361726.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GJB1 | NM_000166.6 | c.307A>G | p.Lys103Glu | missense_variant | 2/2 | ENST00000361726.7 | NP_000157.1 | |
GJB1 | NM_001097642.3 | c.307A>G | p.Lys103Glu | missense_variant | 2/2 | NP_001091111.1 | ||
GJB1 | XM_011530907.3 | c.307A>G | p.Lys103Glu | missense_variant | 2/2 | XP_011529209.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GJB1 | ENST00000361726.7 | c.307A>G | p.Lys103Glu | missense_variant | 2/2 | 1 | NM_000166.6 | ENSP00000354900 | P1 |
Frequencies
GnomAD3 genomes Cov.: 23
GnomAD4 exome AF: 9.17e-7 AC: 1AN: 1090022Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 356438
GnomAD4 genome Cov.: 23
ClinVar
Submissions by phenotype
Charcot-Marie-Tooth Neuropathy X Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 03, 2022 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 429329). This missense change has been observed in individuals with Charcot-Marie-Tooth disease (PMID: 21692908; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 103 of the GJB1 protein (p.Lys103Glu). - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 13, 2024 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; This variant is associated with the following publications: (PMID: 9361298, 21692908, 21291455) - |
Charcot-Marie-Tooth disease Uncertain:1
Uncertain significance, no assertion criteria provided | literature only | Inherited Neuropathy Consortium | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at