Submissions for variant NM_004369.4(COL6A3):c.175C>T (p.Arg59Ter)

gnomAD frequency: 0.00003  dbSNP: rs398124119

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000080916	SCV000331105	pathogenic	not provided	2012-11-05	criteria provided, single submitter	clinical testing
GeneDx	RCV000080916	SCV000680917	uncertain significance	not provided	2023-11-16	criteria provided, single submitter	clinical testing	Reported in an individual with unspecified cardiovascular disease (PMID: 31345219); 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; This variant is associated with the following publications: (PMID: 31589614, 32906206, 31345219, 35925398, 34580720)
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000280500	SCV000845282	pathogenic	Ullrich congenital muscular dystrophy 1A	2018-08-07	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000714578	SCV000845283	pathogenic	Dystonia 27	2018-08-07	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000319162	SCV000845284	pathogenic	Bethlem myopathy 1A	2018-08-07	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000080916	SCV002019678	pathogenic	not provided	2019-09-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000319162	SCV002240853	pathogenic	Bethlem myopathy 1A	2025-01-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg59*) 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 (rs398124119, gnomAD 0.03%). 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: 94911). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Lifecell International Pvt. Ltd	RCV000280500	SCV003842266	likely pathogenic	Ullrich congenital muscular dystrophy 1A		criteria provided, single submitter	clinical testing	A Heterozygous Nonsense variant c.175C>T in Exon 3 of the COL6A3 gene that results in the amino acid substitution p.Arg59* was identified. The observed variant has a maximum allele frequency of 0.00004/0.00006 in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic [Variant ID: 94911]. Loss-of-function variants in COL6A3 are known to be pathogenic. For these reasons, this variant has been classified as Likely pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000280500	SCV004803466	pathogenic	Ullrich congenital muscular dystrophy 1A	2024-01-16	criteria provided, single submitter	clinical testing	Variant summary: COL6A3 c.175C>T (p.Arg59X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 4.4e-05 in 249020 control chromosomes. c.175C>T has been reported in the literature in an unspecified individual affected with Cardiovascular disease trait (example, Glicksberg_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 31345219). ClinVar contains an entry for this variant (Variation ID: 94911). Based on the evidence outlined above, the variant was classified as pathogenic.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000080916	SCV001809060	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000080916	SCV001925064	pathogenic	not provided		no assertion criteria provided	clinical testing