chrX-71224221-C-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000166.6(GJB1):c.514C>T(p.Pro172Ser) 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. P172R) 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 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GJB1 | NM_000166.6 | c.514C>T | p.Pro172Ser | missense_variant | 2/2 | ENST00000361726.7 | |
GJB1 | NM_001097642.3 | c.514C>T | p.Pro172Ser | missense_variant | 2/2 | ||
GJB1 | XM_011530907.3 | c.514C>T | p.Pro172Ser | missense_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GJB1 | ENST00000361726.7 | c.514C>T | p.Pro172Ser | missense_variant | 2/2 | 1 | NM_000166.6 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 22
GnomAD3 exomes AF: 0.00000566 AC: 1AN: 176561Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 62163
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 22
ClinVar
Submissions by phenotype
Charcot-Marie-Tooth Neuropathy X Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 20, 2023 | This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 172 of the GJB1 protein (p.Pro172Ser). This variant is present in population databases (rs104894811, gnomAD 0.005%). This missense change has been observed in individuals with CMTX (PMID: 8266101, 17353473, 21692908). ClinVar contains an entry for this variant (Variation ID: 10432). 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 expected to disrupt GJB1 protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on GJB1 function (PMID: 9592087, 15006706). This variant disrupts the p.Pro172 amino acid residue in GJB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9633821, 9856562, 21692908, 27098783). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2018 | - - |
Charcot-Marie-Tooth disease X-linked dominant 1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 24, 1993 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at