10-49627735-C-T
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_020549.5(CHAT):c.1061C>T(p.Thr354Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000341 in 1,613,940 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_020549.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152236Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251258Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135802
GnomAD4 exome AF: 0.0000349 AC: 51AN: 1461704Hom.: 0 Cov.: 32 AF XY: 0.0000316 AC XY: 23AN XY: 727158
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152236Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74370
ClinVar
Submissions by phenotype
Familial infantile myasthenia Pathogenic:2
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 354 of the CHAT protein (p.Thr354Met). This variant is present in population databases (rs769234940, gnomAD 0.005%). This missense change has been observed in individual(s) with congenital myasthenic syndrome with episodic apnea (PMID: 15701560). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 523528). 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 CHAT protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -
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Lactic acidosis;C0009952:Febrile seizure (within the age range of 3 months to 6 years);C0016202:Pes planus;C0032290:Aspiration pneumonia;C0035229:Respiratory insufficiency;C0162292:External ophthalmoplegia;C0240421:Progressive muscle weakness;C0520680:Apnea, central sleep;C1834015:Progressive ptosis;C1839888:Decreased activity of the pyruvate dehydrogenase complex;C4317146:Gastroesophageal reflux Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at