ClinVar Miner

Submissions for variant NM_004369.4(COL6A3):c.5992C>T (p.Arg1998Ter)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002615961 SCV003505872 pathogenic Bethlem myopathy 1A 2022-11-04 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg1998*) in the COL6A3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COL6A3 are known to be pathogenic (PMID: 26004199). 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. This premature translational stop signal has been observed in individual(s) with clinical features of autosomal recessive COL6A3-related conditions (PMID: 20976770, 32065942). This variant is present in population databases (rs750471097, gnomAD 0.006%).
GeneDx RCV003443130 SCV004167698 likely pathogenic not provided 2023-04-12 criteria provided, single submitter clinical testing 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; Also known as c.5992 C>T p.Arg1998ThrfsX55 due to alternate nomenclature; This variant is associated with the following publications: (PMID: 32065942, 20976770)
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center RCV004784103 SCV005397329 pathogenic Dystonia 27 2022-08-19 criteria provided, single submitter clinical testing This sequence variant is a single nucleotide substitution (C>T) at coding nucleotide 5992 in the COL6A3 gene which changes the Arg1998 codon into an early termition sigl. As it occurs in exon 14 of 44, this variant is predicted to generate a non-functiol allele through the expression of a truncated protein or a loss of COL6A3 expression due to nonsense-mediated decay. This variant has been observed in homozygous state in an individual with neuromuscular disease characterized by torticollis, scoliosis, respiratory complications, and intracellular retention of ColVI protein (PMID: 20976770). This variant is present in 4/282820 alleles (0.001%) in the gnomAD control population dataset. Given the data, we consider this variant to be pathogenic. ACMG Criteria: PM2, PM3, PVS1

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