ClinVar Genomic variation as it relates to human health

Variant summary: COLQ c.1228C>T (p.Arg410Trp) 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 2.8e-05 in 245856 control chromosomes. c.1228C>T has been reported in the literature in multiple individuals affected with Congenital Myasthenic Syndrome. These data indicate that the variant is very likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). Protein truncation variants are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.84). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000381725). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 21952943, 22088788, 25557462, 28024842, 30124556). Different missense changes at the same codon (p.Arg410Gln, p.Arg410Pro) have been reported to be associated with COLQ related disorder (ClinVar ID: VCV000938138 / PMID: 10665486, 14702351). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 22088788, 25557462, 30124556, 21952943, 33487521, 28024842, 37231228, 37721175, 31889643)

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 410 of the COLQ protein (p.Arg410Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with congenital myasthenic syndrome (PMID: 21952943, 22088788, 25557462, 28024842, 30124556). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 381725). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt COLQ protein function with a positive predictive value of 95%. This variant disrupts the p.Arg410 amino acid residue in COLQ. Other variant(s) that disrupt this residue have been observed in individuals with COLQ-related conditions (PMID: 14702351), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.