rs201479289

Variant names:

• chr10-49619743-G-A
• rs201479289
• NM_020549.5:c.406G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PP3_Moderate PP5

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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000078 (0 hom.)
• Consequence: CHAT NM_020549.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7 U:1
• Conservation: PhyloP100: 4.61
• Publications: 17 publications found

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 Gene-Disease associations (from GenCC):

• congenital myasthenic syndrome 6

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• presynaptic congenital myasthenic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• 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 Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 279754.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020549.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHAT	NM_020549.5	MANE Select	c.406G>A	p.Val136Met	missense	Exon 3 of 15	NP_065574.4
	CHAT	NM_001142933.2		c.160G>A	p.Val54Met	missense	Exon 4 of 16	NP_001136405.2
	CHAT	NM_001142929.2		c.52G>A	p.Val18Met	missense	Exon 3 of 15	NP_001136401.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHAT	ENST00000337653.7	TSL:1 MANE Select	c.406G>A	p.Val136Met	missense	Exon 3 of 15	ENSP00000337103.2
	CHAT	ENST00000395562.2	TSL:1	c.160G>A	p.Val54Met	missense	Exon 4 of 16	ENSP00000378929.2
	CHAT	ENST00000339797.5	TSL:1	c.52G>A	p.Val18Met	missense	Exon 3 of 15	ENSP00000343486.1

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152166 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.0000400 AC: 10 AN: 249972 AF XY: 0.0000222

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 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.: 0 Cov.: 32 AF XY: 0.0000743 AC XY: 54 AN XY: 726490

African (AFR) AF: 0.0000598 AC: 2 AN: 33448

American (AMR) AF: 0.0000447 AC: 2 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52702

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5156

European-Non Finnish (NFE) AF: 0.0000890 AC: 99 AN: 1111946

Other (OTH) AF: 0.000166 AC: 10 AN: 60314

GnomAD4 genome AF: 0.0000986 AC: 15 AN: 152166 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74336

African (AFR) AF: 0.0000965 AC: 4 AN: 41432

American (AMR) AF: 0.000131 AC: 2 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000127 Hom.: 0

Bravo AF: 0.0000680

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial infantile myasthenia Pathogenic:4

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.

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

Jun 05, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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:1 Uncertain:1

Aug 21, 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); In silico analysis suggests that this missense variant does not alter protein structure/function; 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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		4.6
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.4	N
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.63
MVP		0.95
MPC		0.89
ClinPred		0.95	D
GERP RS		5.1
Varity_R		0.73
gMVP		0.45
Mutation Taster		=4/96	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs201479289; hg19: chr10-50827789; COSMIC: COSV60320179;