NM_005677.4:c.1082delC

Variant names:

• chr3-15456011-AG-A
• rs769982050
• NM_005677.4:c.1082delC

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 9.09
• Publications: 11 publications found

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

ENSG00000293553 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 3-15456011-AG-A is Pathogenic according to our data. Variant chr3-15456011-AG-A is described in ClinVar as Pathogenic. ClinVar VariationId is 6652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005677.4. 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
	COLQ	NM_005677.4	MANE Select	c.1082delC	p.Pro361LeufsTer65	frameshift	Exon 15 of 17	NP_005668.2
	COLQ	NM_080538.2		c.1052delC	p.Pro351LeufsTer65	frameshift	Exon 15 of 17	NP_536799.1
	COLQ	NM_080539.4		c.980delC	p.Pro327LeufsTer65	frameshift	Exon 14 of 16	NP_536800.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COLQ	ENST00000383788.10	TSL:1 MANE Select	c.1082delC	p.Pro361LeufsTer65	frameshift	Exon 15 of 17	ENSP00000373298.3
	COLQ	ENST00000603808.5	TSL:1	c.1082delC	p.Pro361LeufsTer66	frameshift	Exon 15 of 17	ENSP00000474271.1
	COLQ	ENST00000383781.8	TSL:5	c.1052delC	p.Pro351LeufsTer65	frameshift	Exon 15 of 17	ENSP00000373291.3

Frequencies

GnomAD3 genomes AF: 0.0000921 AC: 14 AN: 152038 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.0000478 AC: 12 AN: 251134 AF XY: 0.0000368

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000657 AC: 96 AN: 1461812 Hom.: 1 Cov.: 32 AF XY: 0.0000701 AC XY: 51 AN XY: 727200

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.000112 AC: 5 AN: 44706

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000755 AC: 84 AN: 1111972

Other (OTH) AF: 0.0000993 AC: 6 AN: 60394

GnomAD4 genome AF: 0.0000921 AC: 14 AN: 152038 Hom.: 0 Cov.: 32 AF XY: 0.0000943 AC XY: 7 AN XY: 74254

African (AFR) AF: 0.0000242 AC: 1 AN: 41382

American (AMR) AF: 0.000524 AC: 8 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

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: 314

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000712 Hom.: 0

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

Submissions by phenotype

Congenital myasthenic syndrome 5 Pathogenic:5

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.

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.

Aug 04, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Sep 05, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Congenital myasthenic syndrome Pathogenic:2

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.

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).

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 v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.1
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs769982050; hg19: chr3-15497518;