Submissions for variant NM_004369.4(COL6A3):c.7447A>G (p.Lys2483Glu)

gnomAD frequency: 0.00057  dbSNP: rs139260335

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000177877	SCV000331642	pathogenic	not provided	2017-04-05	criteria provided, single submitter	clinical testing
GeneDx	RCV000177877	SCV000564904	likely pathogenic	not provided	2025-01-08	criteria provided, single submitter	clinical testing	Reported previously in the compound heterozygous state and in the homozygous state in patients with Bethlem myopathy, hyperCKemia, and Type 1 fiber predominance on muscle biopsy. One patient who was homozygous for this variant also harbored a pathogenic variant in a separate gene; however, segregation studies could not be completed (PMID: 30706156, 32403337, 38155714); Reported previously in patients with with suspected limb girdle muscular dystrophy (PMID: 34720847, 30564623); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 35239206, 26247046, 20576434, 28688748, 29970176, 20976770, 34426522, 33726816, 33596003, 33749658, 32528171, 30487145, 32448721, 32403337, 30564623, 37470033, 36779064, 30706156, 34720847, 37526466, 38127101, 38155714, 36964972, 33441455, 37273706)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000352490	SCV000657402	pathogenic	Bethlem myopathy 1A	2025-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 2483 of the COL6A3 protein (p.Lys2483Glu). This variant is present in population databases (rs139260335, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of autosomal recessive COL6A3-related conditions (PMID: 20976770, 26247046, 28688748, 29970176, 32403337, 32448721, 32528171, 33596003, 33749658; internal data). 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: 196977). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on COL6A3 protein function. For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000352490	SCV001149742	likely pathogenic	Bethlem myopathy 1A	2020-01-14	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000177877	SCV001449836	likely pathogenic	not provided	2016-02-02	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000177877	SCV001962365	likely pathogenic	not provided	2021-09-01	criteria provided, single submitter	clinical testing
Mendelics	RCV000352490	SCV002518761	pathogenic	Bethlem myopathy 1A	2022-05-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003114326	SCV003800970	uncertain significance	not specified	2024-06-27	criteria provided, single submitter	clinical testing	Variant summary: COL6A3 c.7447A>G (p.Lys2483Glu) results in a conservative amino acid change located in the von Willebrand factor, type A (IPR002035) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00061 in 251446 control chromosomes in the gnomAD database, including 1 homozygote. This frequency does not allow conclusions about variant significance. c.7447A>G has been reported in the literature in multiple individuals affected with Limb-girdle muscular dystrophy and in several cases other causes were ruled out by whole exome seqeuencing (e.g., Brinas_2010, Hunter_2015, Sframeli_2017, Nallamilli_2018, Fichna_2018, Villar-Quiles_2021, ). Affected individuals with variant of interest display a relatively mild phenotype (e.g., Bethlem myopathy), often with proximal muscle weakness, skin abnormalities, and joint contractures, however affected indivduals do not seem to experience complete loss of ambulation (Villar-Quiles_2021). Individuals who are homozygous for this variant exhibit different clinical features to those who are compound heterozygous, and some do not have typical COL6-related myopathy phenotypes (Villar-Quiles_2021). The relatively high allele frequency, including a observed homozygous individual in the control population, as well as the different phenotypes observed in the homozygous patients, lead some authors to suggest that this variant may act as a modulator of the clinical phenotype. These authors reccommend using an in-depth analysis of clinical features and ancillary tests in order to interpret the genetic analysis regarding this variant (Villar-Quiles_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 20976770, 29970176, 26247046, 35239206, 30564623, 28688748, 33749658). ClinVar contains an entry for this variant (Variation ID: 196977). Based on the evidence outlined above, the variant was classified as VUS - possibly pathogenic.
Revvity Omics, Revvity	RCV000177877	SCV003829720	likely pathogenic	not provided	2022-08-23	criteria provided, single submitter	clinical testing
Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL)	RCV003387788	SCV003920752	likely pathogenic	COL6A3-related disorder	2023-04-27	criteria provided, single submitter	research
Illumina Laboratory Services, Illumina	RCV003387788	SCV005045493	likely pathogenic	COL6A3-related disorder	2023-05-24	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000177877	SCV005197627	likely pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	RCV004783757	SCV005397330	likely pathogenic	Dystonia 27	2022-08-19	criteria provided, single submitter	clinical testing	This sequence variant is a single nucleotide substitution (A>G) at coding nucleotide 7447 in the COL6A3 gene which results in a lysine to glutamic acid amino acid change at residue 2483 in the COL6A3 protein. This is a previously reported variant (ClinVar) which has been observed in homozygous or compound heterozygous state in several individuals with neuromuscular disorders (PMID: 20976770, 32528171, 32448721, 32403337, 29970176, 28688748, 26247046); in most homozygous cases, the neuromuscular disorders were described as mild with preserved ambulation. This variant is present in 170/282838 alleles (0.06011%), including 1 homozygote, in the gnomAD control population dataset. Structural alysis suggests that this amino acid change will alter the ability of COL6A3 protein to interact with binding targets (PMID: 32448721). Multiple bioinformatic tools predict that this amino acid change will be damaging, and the Lys2483 residue is highly conserved in vertebrates. Functiol studies assessing the effect of this variant on protein structure or activity have not been performed, to our knowledge. Based on the available evidence, we consider this variant to be likely pathogenic. ACMG Criteria: BP1, PM3, PP3, PS4
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000177877	SCV001807700	uncertain significance	not provided		flagged submission	clinical testing
Clinical Genetics, Academic Medical Center	RCV000177877	SCV001920503	uncertain significance	not provided		flagged submission	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003387788	SCV004104265	pathogenic	COL6A3-related disorder	2024-09-04	no assertion criteria provided	clinical testing	The COL6A3 c.7447A>G variant is predicted to result in the amino acid substitution p.Lys2483Glu. This variant has been reported the homozygous and compound heterozygous states in multiple individuals with COL6A3-related myopathies (see for example, Panadés-de Oliveira et al. 2019. PubMed ID: 30706156; Villar-Quiles et al. 2021. PubMed ID: 33749658; Zídková et al. 2023. PubMed ID: 37526466) and has also been shown to co-segregate with disease in multiple families (Hunter et al. 2015. PubMed ID: 26247046; Stavusis et al. 2020. PubMed ID: 32448721; Mihaylova et al. 2021. PubMed ID: 33596003; Villar-Quiles et al. 2021. PubMed ID: 33749658). This variant is reported in 0.10% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Taken together, this variant is interpreted as pathogenic for autosomal recessive COL6A3-related myopathies.
OMIM	RCV004589832	SCV005077970	pathogenic	Bethlem myopathy 1C	2024-07-15	no assertion criteria provided	literature only