NM_000166.6:c.542T>C
Variant summary
Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1PM2PM5PP2PP3_Strong
The NM_000166.6(GJB1):c.542T>C(p.Val181Ala) 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 Uncertain significance (★). 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
Publications
- Charcot-Marie-Tooth disease X-linked dominant 1Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia, ClinGen, Labcorp Genetics (formerly Invitae)
- X-linked progressive cerebellar ataxiaInheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Pathogenic. The variant received 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GJB1 | NM_000166.6 | c.542T>C | p.Val181Ala | missense_variant | Exon 2 of 2 | ENST00000361726.7 | NP_000157.1 | |
GJB1 | NM_001097642.3 | c.542T>C | p.Val181Ala | missense_variant | Exon 2 of 2 | NP_001091111.1 | ||
GJB1 | NM_001440770.1 | c.542T>C | p.Val181Ala | missense_variant | Exon 3 of 3 | NP_001427699.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 21
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 21
ClinVar
Submissions by phenotype
Charcot-Marie-Tooth disease Uncertain:1
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Charcot-Marie-Tooth Neuropathy X Uncertain:1
In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Val181 amino acid residue in GJB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9361298, 17100997, 19259128, 21692908, 25947624). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This variant has been reported to affect GJB1 protein function (PMID: 14627639). This variant has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 14627639). ClinVar contains an entry for this variant (Variation ID: 637559). This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with alanine at codon 181 of the GJB1 protein (p.Val181Ala). The valine residue is highly conserved and there is a small physicochemical difference between valine and alanine. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at