3-15458197-G-A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_005677.4(COLQ):​c.943C>T​(p.Arg315*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,613,612 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 (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

COLQ
NM_005677.4 stop_gained

Scores

2
3
2

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 1.84

Publications

7 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 3-15458197-G-A is Pathogenic according to our data. Variant chr3-15458197-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 6655.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
COLQNM_005677.4 linkc.943C>T p.Arg315* stop_gained Exon 13 of 17 ENST00000383788.10 NP_005668.2 Q9Y215-1
COLQNM_080538.2 linkc.913C>T p.Arg305* stop_gained Exon 13 of 17 NP_536799.1 Q9Y215-2
COLQNM_080539.4 linkc.841C>T p.Arg281* stop_gained Exon 12 of 16 NP_536800.2 Q9Y215-3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
COLQENST00000383788.10 linkc.943C>T p.Arg315* stop_gained Exon 13 of 17 1 NM_005677.4 ENSP00000373298.3 Q9Y215-1
COLQENST00000603808.5 linkc.943C>T p.Arg315* stop_gained Exon 13 of 17 1 ENSP00000474271.1 A0A0C4DGS2

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152134
Hom.:
0
Cov.:
32
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000159
AC:
4
AN:
251456
AF XY:
0.0000147
show subpopulations
Gnomad AFR exome
AF:
0.0000615
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:
0.0000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000116
AC:
17
AN:
1461478
Hom.:
0
Cov.:
31
AF XY:
0.0000110
AC XY:
8
AN XY:
727044
show subpopulations
African (AFR)
AF:
0.0000299
AC:
1
AN:
33472
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39698
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86230
European-Finnish (FIN)
AF:
0.0000187
AC:
1
AN:
53420
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5450
European-Non Finnish (NFE)
AF:
0.0000117
AC:
13
AN:
1112000
Other (OTH)
AF:
0.0000331
AC:
2
AN:
60348
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.440
Heterozygous variant carriers
0
1
2
4
5
6
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152134
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74310
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41432
American (AMR)
AF:
0.00
AC:
0
AN:
15276
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5188
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4816
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10612
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68022
Other (OTH)
AF:
0.00
AC:
0
AN:
2090
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.575
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0000479
Hom.:
0
Bravo
AF:
0.0000113
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Congenital myasthenic syndrome 5 Pathogenic:5
Feb 12, 2020
Revvity Omics, Revvity
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

May 18, 2018
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

A homozygous nonsense variant, NM_005677.3(COLQ):c.943C>T, has been identified in exon 13 of 17 of the COLQ gene. The variant is predicted to result in a premature stop codon at position 315 of the protein, NP_005668.2(COLQ):p.(Arg315*). This variant is predicted to result in loss of protein function either through truncation (including the C-terminal end region) or nonsense-mediated decay, which is a reported mechanism of pathogenicity for this gene. The variant is present in the gnomAD database at a frequency of 0.0016% (4 heterozygotes, 0 homozygotes). The variant has been previously described as pathogenic and segregated with disease in three affected members of a family (ClinVar, Ohno et al., (1999)). Additionally, functional analysis of the congenital end-pate acetylcholinesterase (AChE) showed reduced expression preventing the anchoring of the AChE to the synaptic basal lamina (Ohno et al., (1999)). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC. -

Sep 01, 1999
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

Mar 24, 2024
Baylor Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jun 04, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is present in population databases (rs121908924, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.Arg315*) in the COLQ gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COLQ are known to be pathogenic (PMID: 22678886). This premature translational stop signal has been observed in individuals with congenital myasthenic syndrome (PMID: 10441569). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 6655). -

not provided Pathogenic:2
Nov 04, 2016
Athena Diagnostics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Dec 12, 2024
GeneDx
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Published functional studies demonstrate a damaging effect, as the variant caused the failure of forming the expected AChE complexes (PMID: 10441569); Observed with another variant in the COLQ gene in a patient with AChE deficiency in published literature; however, it is unclear whether the variants were on the same (in cis) or on opposite alleles (in trans) (PMID: 10441569); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 32573669, 10441569) -

Synaptic congenital myasthenic syndromes Pathogenic:1
Jan 01, 2023
Neuromuscular Department, Shariati Hospital, Tehran University of Medical Sciences
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.50
D
BayesDel_noAF
Pathogenic
0.35
CADD
Pathogenic
40
DANN
Uncertain
1.0
Eigen
Uncertain
0.41
Eigen_PC
Benign
0.19
FATHMM_MKL
Uncertain
0.85
D
PhyloP100
1.8
Vest4
0.85
GERP RS
2.8
Mutation Taster
=0/200
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.40
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.40
Position offset: 2

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

Publications

Other links and lift over

dbSNP: rs121908924; hg19: chr3-15499704; API