rs1555937122
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000166.6(GJB1):c.266T>C(p.Leu89Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. L89V) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000166.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GJB1 | NM_000166.6 | c.266T>C | p.Leu89Pro | missense_variant | 2/2 | ENST00000361726.7 | |
GJB1 | NM_001097642.3 | c.266T>C | p.Leu89Pro | missense_variant | 2/2 | ||
GJB1 | XM_011530907.3 | c.266T>C | p.Leu89Pro | missense_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GJB1 | ENST00000361726.7 | c.266T>C | p.Leu89Pro | missense_variant | 2/2 | 1 | NM_000166.6 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 23
ClinVar
Submissions by phenotype
Charcot-Marie-Tooth Neuropathy X Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2017 | This sequence change replaces leucine with proline at codon 89 of the GJB1 protein (p.Leu89Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. Experimental studies have found that this missense change impacts the cellular localization of the GJB1-encoded CX32 protein, preventing the formation of functional CX32 gap junctions (PMID: 27367520). This variant has been reported in multiple individuals affected with CMTX1 (PMID: 26274329, 12457340, 9099841) and it has been reported to segregate with disease in a family affected with X-linked dominant Charcot-Marie-Tooth disease (CMTX1) (PMID: 17714866). This variant is also known as leu238pro in the literature. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Dec 13, 2016 | - - |
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