rs876661269
Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PS1PM1PM2PP3_StrongPP5_Very_Strong
The NM_000166.6(GJB1):c.151T>C(p.Phe51Leu) 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 Likely pathogenic (★★). 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. F51S) has been classified as Uncertain significance.
Frequency
Consequence
NM_000166.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GJB1 | NM_000166.6 | c.151T>C | p.Phe51Leu | missense_variant | 2/2 | ENST00000361726.7 | |
GJB1 | NM_001097642.3 | c.151T>C | p.Phe51Leu | missense_variant | 2/2 | ||
GJB1 | XM_011530907.3 | c.151T>C | p.Phe51Leu | missense_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GJB1 | ENST00000361726.7 | c.151T>C | p.Phe51Leu | missense_variant | 2/2 | 1 | NM_000166.6 | P1 |
Frequencies
GnomAD3 genomes Cov.: 22
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 22
ClinVar
Submissions by phenotype
not provided Pathogenic:4
Likely pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 30, 2016 | A F51L variant that is likely pathogenic has been identified in the GJB1 gene. The F51L variant has been reported previously in an individual with CMT and was not detected in 200 control individuals; however, information about parental testing was not provided and functional characterization of the variant was not performed (Wang et al., 2015). The F51L variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The F51L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, multiple missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with CMT neuropathy (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. - |
Likely pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Mar 21, 2022 | This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. Protein containing this variant does not properly traffic to the plasma membrane and therefore cannot form functional gap junctions (PMID: 28071741). - |
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 10, 2021 | The p.F51L variant (also known as c.151T>C), located in coding exon 1 of the GJB1 gene, results from a T to C substitution at nucleotide position 151. The phenylalanine at codon 51 is replaced by leucine, an amino acid with highly similar properties. This alteration has been observed in multiple individuals with a personal and/or family history that is consistent with Charcot-Marie-Tooth disease (Wang R et al. Clin Chim Acta, 2015 Dec;451:263-70; Abrams CK et al. Sci Rep, 2017 01;7:40166; Panosyan FB et al. Neurology, 2017 Aug;89:927-935; Chen CX et al. Clin Genet, 2019 11;96:439-448; Ambry internal data). In one experimental study, this alteration appeared to impair gap junction formation (Abrams CK et al. Sci Rep, 2017 01;7:40166). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Charcot-Marie-Tooth Neuropathy X Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 22, 2023 | This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 51 of the GJB1 protein (p.Phe51Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Charcot-Marie-Tooth disease (PMID: 26454100, 28071741; Invitae). ClinVar contains an entry for this variant (Variation ID: 234871). 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 not expected to disrupt GJB1 protein function. Experimental studies have shown that this missense change affects GJB1 function (PMID: 28071741). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at