rs201479289

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_020549.5(CHAT):c.406G>A(p.Val136Met) variant causes a missense change. The variant allele was found at a frequency of 0.00008 in 1,612,480 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

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000078 ( 0 hom. )

Consequence

CHAT
NM_020549.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7U:1

Conservation

PhyloP100: 4.61

Variant links:

Genes affected

CHAT (HGNC:1912): (choline O-acetyltransferase) This gene encodes an enzyme which catalyzes the biosynthesis of the neurotransmitter acetylcholine. This gene product is a characteristic feature of cholinergic neurons, and changes in these neurons may explain some of the symptoms of Alzheimer's disease. Polymorphisms in this gene have been associated with Alzheimer's disease and mild cognitive impairment. Mutations in this gene are associated with congenital myasthenic syndrome associated with episodic apnea. Multiple transcript variants encoding different isoforms have been found for this gene, and some of these variants have been shown to encode more than one isoform. [provided by RefSeq, May 2010]

CHAT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.863

PP5

Variant 10-49619743-G-A is Pathogenic according to our data. Variant chr10-49619743-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 279754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-49619743-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHAT	NM_020549.5 link	c.406G>A	p.Val136Met	missense_variant	Exon 3 of 15	ENST00000337653.7	NP_065574.4	P28329-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHAT	ENST00000337653.7 link	c.406G>A	p.Val136Met	missense_variant	Exon 3 of 15	1	NM_020549.5	ENSP00000337103.2		P28329-1

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000400

AC:

AN:

249972

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

135274

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000618

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000781

AC:

114

AN:

1460314

Hom.:

Cov.:

AF XY:

0.0000743

AC XY:

AN XY:

726490

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000890

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.0000986

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000122

Hom.:

Bravo

AF:

0.0000680

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial infantile myasthenia

Pathogenic:4

Jun 05, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 19, 2023

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 20, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 136 of the CHAT protein (p.Val136Met). This variant is present in population databases (rs201479289, gnomAD 0.02%). This missense change has been observed in individual(s) with congenital myasthenic syndrome (PMID: 21786365, 26080897, 28497657; internal data). 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: 279754). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CHAT protein function. Experimental studies have shown that this missense change affects CHAT function (PMID: 21786365, 26080897). For these reasons, this variant has been classified as Pathogenic. -

Congenital myasthenic syndrome

Pathogenic:2

May 10, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Val54Met variant in CHAT has been reported in four patients with congenita l myasthenic syndrome with episodic apnea (three compound heterozygotes and one homozygote) (Shen 2011, Arredondo 2015). This variant has also been identified i n 5/118276 of chromosomes by the Exome Aggregation Consortium (ExAC, http://exac .broadinstitute.org; dbSNP rs201479289). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a rece ssive carrier frequency. In vitro functional studies provide some evidence that the p.Val54Met variant may impact protein function (Shen 2011, Arredondo 2015). However, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its cli nical significance, the p.Val54Met variant is likely pathogenic. -

Jan 24, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CHAT c.406G>A (p.Val136Met) results in a conservative amino acid change located in the Choline/carnitine acyltransferase domain (IPR039551) of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 250372 control chromosomes (gnomAD and publication data). This frequency is not significantly higher than expected for a pathogenic variant in CHAT causing Congenital Myasthenic Syndrome (4e-05 vs 0.00079), allowing no conclusion about variant significance. c.406G>A has been reported in the literature in multiple individuals affected with Congenital Myasthenic Syndrome, including at least one homozygote (Shen_2011, Abicht_2012, Arredondo_2015). These data indicate that the variant is very likely to be associated with disease. Functional studies report this variant results in reducing protein expression level and catalytic efficiency of the enzyme (Shen_2011, Arredondo_2015). Five ClinVar submitters (evaluation after 2014) cite this variant as pathogenic (n=2), likely pathogenic (n=2) and uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:1Uncertain:1

Feb 04, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate decreased protein expression, as well as reduced catalytic efficiency of the enzyme (PMID: 21786365, 26080897); This variant is associated with the following publications: (PMID: 28497657, 29783273, 31192527, 31980526, 21786365, 26080897, 29759072, 30609409, 34426522, 34557490, 30458023) -

Dec 21, 2015

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.81

.;.;.;D;.

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.82

LIST_S2

Pathogenic

0.97

.;.;D;D;D

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.86

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.8

.;.;.;H;.

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-2.4

N;N;N;N;N

REVEL

Pathogenic

0.80

Sift

Uncertain

0.0010

D;D;D;D;D

Sift4G

Uncertain

0.0030

D;D;D;D;D

Polyphen

1.0

.;.;.;D;.

Vest4

0.63

MVP

0.95

MPC

0.89

ClinPred

0.95

GERP RS

5.1

Varity_R

0.73

gMVP

0.45

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over