chrX-71224248-G-T
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS1PM1PM2PM5PP3_Moderate
The NM_000166.6(GJB1):c.541G>T(p.Val181Leu) variant causes a missense change involving the alteration of a non-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 Uncertain significance (★). 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. V181E) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000166.6 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GJB1 | NM_000166.6 | c.541G>T | p.Val181Leu | missense_variant | 2/2 | ENST00000361726.7 | |
GJB1 | NM_001097642.3 | c.541G>T | p.Val181Leu | missense_variant | 2/2 | ||
GJB1 | XM_011530907.3 | c.541G>T | p.Val181Leu | missense_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GJB1 | ENST00000361726.7 | c.541G>T | p.Val181Leu | missense_variant | 2/2 | 1 | NM_000166.6 | P1 |
Frequencies
GnomAD3 genomes Cov.: 21
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1093879Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 360927
GnomAD4 genome Cov.: 21
ClinVar
Submissions by phenotype
Charcot-Marie-Tooth Neuropathy X Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 08, 2016 | This missense change is located in a region of the GJB1 protein where a significant number of previously reported GJB1 missense mutations are found (PMID: 9361298, 20128140, 17100997, 16922730,15006706,9187667). These observations suggest that a previously unreported missense substitution within this region may affect protein function, but experiments have not been done to test this possibility. This sequence change replaces valine with leucine at codon 181 of the GJB1 protein (p.Val181Leu). The valine residue is highly conserved and there is a small physicochemical difference between valine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with Charcot-Marie-Tooth disease type X (PMID: 18380031). A different missense substitution at this codon (p.Val181Ala) has been determined to be pathogenic (PMID: 14627639). In addition, a different missense substitution at this codon (p.Val181Met) has been reported in a patient with Charcot-Marie-Tooth disease type X (PMID: 9361298). This suggests that the valine residue is critical for GJB1 protein function and that other missense substitutions at this position may also be pathogenic. In summary, this variant is a rare missense change with uncertain impact on protein function. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at