Submissions for variant NM_004369.4(COL6A3):c.2506C>T (p.Arg836Ter)

dbSNP: rs761796175

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000482545	SCV000567251	pathogenic	not provided	2015-07-28	criteria provided, single submitter	clinical testing	The R836X non-sense variant in the COL6A3 gene has not been reported previously as a pathogenic variant nor as a benign polymorphism, to our knowledge. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R836X mutation was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret R836X as a pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000704208	SCV000833147	pathogenic	Bethlem myopathy 1A	2025-01-07	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg836*) 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). This variant is present in population databases (rs761796175, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with COL6A3-related conditions. ClinVar contains an entry for this variant (Variation ID: 419449). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000482545	SCV002019672	pathogenic	not provided	2019-01-31	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224805	SCV003920877	likely pathogenic	Bethlem myopathy 1A; Ullrich congenital muscular dystrophy 1A; Dystonia 27	2021-03-30	criteria provided, single submitter	clinical testing	COL6A3 NM_004369.3 exon 7 p.Arg836* (c.2506C>T): This variant has not been reported in the literature and is present in 0.0008% (1/112246) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/2-238285979-G-A). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is present in ClinVar (Variation ID:419449). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is predicted to cause a stopgain at this codon, resulting in protein truncation or loss of allelic expression through nonsense-mediated mRNA decay. Loss of function variants have been reported in association with disease for this gene (Brinas 2010 PMID:20976770). In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant is classified as likely pathogenic.
Genetics Department, Catlab	RCV004797817	SCV005419269	pathogenic	Bethlem myopathy 1C; Ullrich congenital muscular dystrophy 1C	2024-05-15	criteria provided, single submitter	clinical testing	The c.2506C>T variant in the COL6A3 gene is a nonsense variant predicted to undergo nonsense mediated decay and loss of function variants have been described as a causing mechanism for the gene (PVS1). The variant is extremely rare in gnomAD 4.1 (AF= 0.000005) (PM2). With all the available evidence, the variant is classified as likely pathogenic.