NM_005677.4:c.1289A>C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1PP2PP3_ModeratePP5_Very_Strong

The NM_005677.4(COLQ):c.1289A>C(p.Tyr430Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000199 in 1,608,320 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 Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

COLQ
NM_005677.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 7.76

Publications

11 publications found

Variant links:

Genes affected

COLQ (HGNC:2226): (collagen like tail subunit of asymmetric acetylcholinesterase) This gene encodes the subunit of a collagen-like molecule associated with acetylcholinesterase in skeletal muscle. Each molecule is composed of three identical subunits. Each subunit contains a proline-rich attachment domain (PRAD) that binds an acetylcholinesterase tetramer to anchor the catalytic subunit of the enzyme to the basal lamina. Mutations in this gene are associated with endplate acetylcholinesterase deficiency. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

COLQ Gene-Disease associations (from GenCC):

congenital myasthenic syndrome 5
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, PanelApp Australia

COLQ links:

ENSG00000293553 (HGNC:):

ENSG00000293553 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 13 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 2 uncertain in NM_005677.4

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 16 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Gene score misZ: -0.21928 (below the threshold of 3.09). Trascript score misZ: -0.17745 (below the threshold of 3.09). GenCC associations: The gene is linked to congenital myasthenic syndrome 5.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.934

PP5

Variant 3-15453838-T-G is Pathogenic according to our data. Variant chr3-15453838-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 6654.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COLQ	NM_005677.4 link	c.1289A>C	p.Tyr430Ser	missense_variant	Exon 16 of 17	ENST00000383788.10	NP_005668.2	Q9Y215-1
COLQ	NM_080538.2 link	c.1259A>C	p.Tyr420Ser	missense_variant	Exon 16 of 17		NP_536799.1	Q9Y215-2
COLQ	NM_080539.4 link	c.1187A>C	p.Tyr396Ser	missense_variant	Exon 15 of 16		NP_536800.2	Q9Y215-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
COLQ	ENST00000383788.10 link	c.1289A>C	p.Tyr430Ser	missense_variant	Exon 16 of 17	1	NM_005677.4	ENSP00000373298.3	Q9Y215-1
COLQ	ENST00000603808.5 link	c.1292A>C	p.Tyr431Ser	missense_variant	Exon 16 of 17	1		ENSP00000474271.1	A0A0C4DGS2
ENSG00000293553	ENST00000629729.3 link	n.*13A>C		non_coding_transcript_exon_variant	Exon 2 of 6	5		ENSP00000518887.1
ENSG00000293553	ENST00000629729.3 link	n.*13A>C		3_prime_UTR_variant	Exon 2 of 6	5		ENSP00000518887.1

Frequencies

GnomAD3 genomes

AF:

0.0000461

AC:

AN:

151894

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000408

AC:

AN:

245298

AF XY:

0.0000377

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000146

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000452

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000172

AC:

AN:

1456426

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

724354

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33322

American (AMR)

AF:

0.000135

AC:

AN:

44442

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26022

East Asian (EAS)

AF:

0.00

AC:

AN:

39496

South Asian (SAS)

AF:

0.00

AC:

AN:

85376

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53156

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.0000153

AC:

AN:

1108674

Other (OTH)

AF:

0.0000166

AC:

AN:

60188

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000461

AC:

AN:

151894

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74176

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41344

American (AMR)

AF:

0.000393

AC:

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10586

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67946

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000312

Hom.:

Bravo

AF:

0.0000756

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Congenital myasthenic syndrome 5

Pathogenic:6

Nov 10, 2023

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 v2.1.1 dataset (total allele frequency: 0.004%). Predicted Consequence/Location: Missense variant Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 15159418). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.92 (>=0.6, sensitivity 0.68 and specificity 0.92)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000006654 /PMID: 9758617).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 (PMID: 29054425). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Oct 01, 1998

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Mar 10, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 30, 2019

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with serine, which is neutral and polar, at codon 430 of the COLQ protein (p.Tyr430Ser). This variant is present in population databases (rs121908923, gnomAD 0.02%). This missense change has been observed in individuals with congenital myasthenic syndrome (PMID: 9758617, 29054425). It has also been observed to segregate with disease in related individuals. This variant is also known as Y431S. ClinVar contains an entry for this variant (Variation ID: 6654). 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 not expected to disrupt COLQ protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects COLQ function (PMID: 15159418). For these reasons, this variant has been classified as Pathogenic. -

Mar 19, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Slow-Channel Congenital Myasthenia Syndrome

Pathogenic:1

Jan 05, 2022

DASA

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1289A>C;p.(Tyr430Ser) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 6654; PMID: 29054425) - PS4.The variant is present at low allele frequencies population databases (rs121908923– gnomAD 0.0004608%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Tyr430Ser) was detected in trans with a pathogenic variant (PMID: 29054425) - PM3_strong. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. -

COLQ-related disorder

Pathogenic:1

Sep 26, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The COLQ c.1289A>C variant is predicted to result in the amino acid substitution p.Tyr430Ser. This variant has been reported in the homozygous state in several siblings in a large family to be causative for congenital myasthenic syndrome (Donger et al. 1998. PubMed ID: 9758617). This variant has also been reported in the compound heterozygous state in several additional individuals with congenital myasthenic syndrome (Servais et al. 2012. PubMed ID: 23108489; Natera-de Benito et al. 2017. PubMed ID: 29054425). This variant is reported in 0.017% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic. -

Congenital myasthenic syndrome

Pathogenic:1

Mar 18, 2024

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: COLQ c.1289A>C (p.Tyr430Ser) results in a non-conservative amino acid change in 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 4.1e-05 in 245298 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in COLQ causing Congenital Myasthenic Syndrome (4.1e-05 vs 0.0014), allowing no conclusion about variant significance. c.1289A>C has been reported in the literature in multiple homozygous individuals affected with Congenital Myasthenic Syndrome (e.g. Abicht_2012). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 22678886). ClinVar contains an entry for this variant (Variation ID: 6654). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.45

CADD

Pathogenic

(source)

DANN

Benign

0.97

DEOGEN2

Uncertain

0.47

T;.;.;.

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.96

D;D;D;D

M_CAP

Pathogenic

0.62

MetaRNN

Pathogenic

0.93

D;D;D;D

MetaSVM

Pathogenic

0.95

MutationAssessor

Uncertain

2.3

M;.;.;.

PhyloP100

7.8

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.9

N;N;.;N

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

D;D;.;.

Sift4G

Pathogenic

0.0010

D;D;D;D

Polyphen

1.0

D;D;.;D

Vest4

0.87

MutPred

0.80

Gain of disorder (P = 0.0175);.;.;.;

MVP

1.0

MPC

0.14

ClinPred

0.28

GERP RS

5.4

Varity_R

0.53

gMVP

0.93

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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NM_005677.4:c.1289A>C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over