Submissions for variant NM_005677.4(COLQ):c.1082del (p.Pro361fs)

dbSNP: rs769982050

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000727941	SCV000855455	pathogenic	not provided	2017-07-10	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825560	SCV000966885	pathogenic	Congenital myasthenic syndrome	2018-01-10	criteria provided, single submitter	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).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000007031	SCV001588904	pathogenic	Congenital myasthenic syndrome 5	2023-07-31	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 6652). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the COLQ protein in which other variant(s) (p.Cys427*) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This premature translational stop signal has been observed in individuals with congenital myasthenic syndrome (PMID: 9689136, 23371844, 28464723). This variant is present in population databases (rs769982050, gnomAD 0.02%). 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.
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001813960	SCV001755170	pathogenic	Abnormality of the musculature	2021-07-10	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000007031	SCV002019702	pathogenic	Congenital myasthenic syndrome 5	2021-09-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000825560	SCV002570798	pathogenic	Congenital myasthenic syndrome	2022-07-15	criteria provided, single submitter	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.
Baylor Genetics	RCV000007031	SCV004214436	pathogenic	Congenital myasthenic syndrome 5	2024-03-23	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV000007031	SCV004812615	pathogenic	Congenital myasthenic syndrome 5	2023-06-15	criteria provided, single submitter	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.
OMIM	RCV000007031	SCV000027227	pathogenic	Congenital myasthenic syndrome 5	1998-08-04	no assertion criteria provided	literature only