rs121912819

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_020549.5(CHAT):c.1679G>A(p.Arg560His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000657 in 1,613,904 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000070 ( 0 hom. )

Consequence

CHAT
NM_020549.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:4

Conservation

PhyloP100: 10.0

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 Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.877

PP5

Variant 10-49655139-G-A is Pathogenic according to our data. Variant chr10-49655139-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 17510.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=1, Pathogenic=1}. Variant chr10-49655139-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.1679G>A	p.Arg560His	missense_variant	Exon 12 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.1679G>A	p.Arg560His	missense_variant	Exon 12 of 15	1	NM_020549.5	ENSP00000337103.2		P28329-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000875

AC:

AN:

251294

Hom.:

AF XY:

0.0000810

AC XY:

AN XY:

135872

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00129

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000698

AC:

102

AN:

1461832

Hom.:

Cov.:

AF XY:

0.0000743

AC XY:

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00115

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000558

Gnomad4 OTH exome

AF:

0.0000993

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152072

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74276

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000133

Hom.:

Bravo

AF:

0.0000604

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000988

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial infantile myasthenia

Pathogenic:4

Oct 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 560 of the CHAT protein (p.Arg560His). This variant is present in population databases (rs121912819, gnomAD 0.1%). This missense change has been observed in individuals with clinical features of congenital myasthenic syndrome (PMID: 11172068; internal data). This variant is also known as R442H. ClinVar contains an entry for this variant (Variation ID: 17510). 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) indicates that this missense variant is expected to disrupt CHAT protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects CHAT function (PMID: 11172068, 15381704). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Mar 07, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 30, 2024

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v4.0.0 dataset (total allele frequency: 0.007%). Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 11172068, 15381704). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.94 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.92 (>=0.6, sensitivity 0.72 and precision 0.9)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000017510 / PMID: 11172068). A different missense change at the same codon (p.Arg560Cys) has been reported to be associated with CHAT related disorder (ClinVar ID: VCV002993039). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (3billion database). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Feb 13, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided

Pathogenic:1Uncertain:3

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 27, 2022

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Previously reported in an individual with CMS who had a second CHAT variant, however segregation data was not provided (Ohno et al., 2001); Published functional studies demonstrate that this variant results in lack of catalytic efficiency of the ChAT enzyme (Ohno et al., 2001; Albers et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 26080897, 11172068, 19688192, 24844149, 15131697, 33650116, 15381704, 15477102, 29783273) -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Uncertain:1

Jun 13, 2022

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CHAT c.1679G>A (p.Arg560His) results in a non-conservative amino acid change located in the Choline/carnitine acyltransferase domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.8e-05 in 251294 control chromosomes, predominantly at a frequency of 0.0013 within the Ashkenazi Jewish subpopulation in the gnomAD database. The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in CHAT causing Congenital Myasthenic Syndrome phenotype (0.00079), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Ashkenazi Jewish origin. c.1679G>A has been reported in the literature in one individual affected with Congenital Myasthenic Syndrome (Ohno_2001). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Ohno_2001, Dobransky_2004). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.88

.;.;.;D;.;.

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

.;.;D;D;D;D

M_CAP

Pathogenic

0.43

MetaRNN

Pathogenic

0.88

D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.0

.;.;.;H;.;.

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-5.0

D;D;D;D;D;.

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

D;D;D;D;D;.

Sift4G

Uncertain

0.0020

D;D;D;D;D;.

Polyphen

1.0

.;.;.;D;.;.

Vest4

0.96

MVP

0.99

MPC

1.0

ClinPred

0.99

GERP RS

5.4

Varity_R

0.93

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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