NM_005677.4:c.1082delC

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_005677.4(COLQ):c.1082delC(p.Pro361LeufsTer65) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000682 in 1,613,850 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000066 ( 1 hom. )

Consequence

COLQ
NM_005677.4 frameshift

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 9.09

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 links:

EAF1-AS1 (HGNC:42328): (EAF1 antisense RNA 1)

EAF1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 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 3-15456011-AG-A is Pathogenic according to our data. Variant chr3-15456011-AG-A is described in ClinVar as [Pathogenic]. Clinvar id is 6652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15456011-AG-A is described in Lovd as [Pathogenic]. Variant chr3-15456011-AG-A is described in Lovd as [Pathogenic]. Variant chr3-15456011-AG-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COLQ	NM_005677.4 link	c.1082delC	p.Pro361LeufsTer65	frameshift_variant	Exon 15 of 17	ENST00000383788.10	NP_005668.2	Q9Y215-1
COLQ	NM_080538.2 link	c.1052delC	p.Pro351LeufsTer65	frameshift_variant	Exon 15 of 17		NP_536799.1	Q9Y215-2
COLQ	NM_080539.4 link	c.980delC	p.Pro327LeufsTer65	frameshift_variant	Exon 14 of 16		NP_536800.2	Q9Y215-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
COLQ	ENST00000383788.10 link	c.1082delC	p.Pro361LeufsTer65	frameshift_variant	Exon 15 of 17	1	NM_005677.4	ENSP00000373298.3	Q9Y215-1
COLQ	ENST00000603808.5 link	c.1082delC	p.Pro361LeufsTer66	frameshift_variant	Exon 15 of 17	1		ENSP00000474271.1	A0A0C4DGS2
EAF1-AS1	ENST00000629729.2 link	n.-72delC		upstream_gene_variant		5		ENSP00000518887.1

Frequencies

GnomAD3 genomes

AF:

0.0000921

AC:

AN:

152038

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000478

AC:

AN:

251134

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135754

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000174

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:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000657

AC:

AN:

1461812

Hom.:

Cov.:

AF XY:

0.0000701

AC XY:

AN XY:

727200

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000755

Gnomad4 OTH exome

AF:

0.0000993

GnomAD4 genome

AF:

0.0000921

AC:

AN:

152038

Hom.:

Cov.:

AF XY:

0.0000943

AC XY:

AN XY:

74254

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.000524

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000567

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Congenital myasthenic syndrome 5

Pathogenic:5

Sep 05, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 15, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change in COLQ is a frameshift variant that may cause a premature stop codon, p.(Pro361Leufs*65), that is predicted to escape nonsense-mediated decay and remove <10% of the protein, however, it is a truncation of a functionally important region (removes amino acids 416-433) in a gene where loss of function is an established disease mechanism (PMID: 9689136). The highest population minor allele frequency in the population database gnomAD v2.1 is 0.017% (6/35,406 alleles) in the Latino/Admixed American population, which is consistent with recessive disease. This variant has been detected in at least 15 individuals with congenital myasthenic syndrome. Of those individuals, 10 were homozygous and five were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and two of those were confirmed in trans by family testing (PMID: 9689136, 10665486, 18180250, 21952943, 22088788, 22678886, 23371844, 29150079). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PVS1_Strong, PM2_Supporting. -

Aug 04, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 23, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Pro361Leufs*65) in the COLQ gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 95 amino acid(s) of the COLQ protein. This variant is present in population databases (rs769982050, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with congenital myasthenic syndrome (PMID: 9689136, 23371844, 28464723). ClinVar contains an entry for this variant (Variation ID: 6652). This variant disrupts a region of the COLQ protein in which other variant(s) (p.Cys427*) have been determined to be pathogenic (internal data). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Congenital myasthenic syndrome

Pathogenic:2

Jan 10, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Pro361fs variant in COLQ has been reported in at least 8 individuals (2 co mpound heterozygotes and 6 homozygotes) with clinical features of congenital mya sthenic syndrome (Ohno 1998, Abicht 2012, Arredondo 2014). This variant has been identified in 0.004% (5/126540) of European chromosomes by the Genome Aggregati on Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs769982050). In vi tro functional studies provide some evidence that the p.Pro361fs variant may imp act protein function (Ohno 1998). This variant is predicted to cause a frameshif t, which alters the protein?s amino acid sequence beginning at position 361 and leads to a premature termination codon 65 amino acids downstream. This alteratio n is then predicted to lead to a truncated or absent protein. In summary, this v ariant meets criteria to be classified as pathogenic for congenital myasthenic s yndrome in an autosomal recessive manner based upon case studies, low frequency in controls, functional evidence, predicted impact on protein. ACMG/AMP Criteria applied: PVS1, PM2, PM3, PS3_P (Richards 2015). -

Jul 15, 2022

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.1082delC (p.Pro361LeufsX65) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been associated with Endplate acetylcholinesterase deficiency in HGMD and are classified as pathogenic in ClinVar. The variant allele was found at a frequency of 4.8e-05 in 251134 control chromosomes (gnomAD). c.1082delC has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Congenital Myasthenic Syndrome (examples: Ohno_1998 and Abicht_2012). Additionally, using in-vitro functional studies Ohno et al (1998) demonstrated that this variant affects protein function. These data indicate that the variant is very likely to be associated with disease. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:1

Jul 10, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Abnormality of the musculature

Pathogenic:1

Jul 10, 2021

Kariminejad - Najmabadi Pathology & Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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