ClinVar Miner

Submissions for variant NM_004369.3(COL6A3):c.7447A>G (p.Lys2483Glu) (rs139260335)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000177877 SCV000331642 pathogenic not provided 2017-04-05 criteria provided, single submitter clinical testing
GeneDx RCV000177877 SCV000564904 likely pathogenic not provided 2019-01-02 criteria provided, single submitter clinical testing A variant that is likely pathogenic has been identified in the COL6A3 gene. The K2483E variant has been reported previously in both homozygous and compound heterozygous patients with COL6A3-related disorders (Briñas et al., 2010; Deconinck et al., 2010; Hunter et al., 2015; Sframeli et al., 2017). The K2483E variant is observed in 132/126672 (0.1%) alleles from individuals of European background, including 1 homozygous individual in largepopulation cohorts (Lek et al., 2016). The K2483E variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size, and/or other properties. Additionally, this substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent inits predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae RCV000352490 SCV000657402 uncertain significance Bethlem myopathy 1 2020-01-02 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamic acid at codon 2483 of the COL6A3 protein (p.Lys2483Glu). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is present in population databases (rs139260335, ExAC 0.09%), including at least one homozygous and/or hemizygous individual. This variant has been reported in the compound heterozygous or homozygous state in individuals affected with early-onset myopathy and congenital muscular dystrophy (PMID: 20976770, 26247046, 28688748, 29970176) and in the heterozygous state in an individual with clinical suspicion of limb-girdle muscular dystrophy (PMID: 30564623) as well as in a reportedly healthy individual (PMID: 30487145). ClinVar contains an entry for this variant (Variation ID: 196977). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Illumina Clinical Services Laboratory,Illumina RCV000779316 SCV000915899 uncertain significance Collagen VI-related myopathy 2017-04-28 criteria provided, single submitter clinical testing The COL6A3 c.7447A>G (p.Lys2483Glu) variant has been reported in four unrelated individuals with various collagen type VI-related muscle disorders, including including in one patient who was homozygous for the variant, in two patients who were compound heterozygous for the variant and a second known pathogenic variant, and one patient who was heterozygous but also compound heterozygous for two variants in the COL6A6 gene (Briñas et al. 2010; Hunter et al. 2015). The p.Lys2483Glu variant was also detected in a heterozygous state in six unaffected family members. Control data are unavailable for this variant, which is reported at a frequency of 0.000929 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence, the p.Lys2483Glu variant is classified as a variant of unknown significance but suspicious for pathogenicity for collagen type VI-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Institute of Human Genetics,Klinikum rechts der Isar RCV000352490 SCV001149742 likely pathogenic Bethlem myopathy 1 2020-01-14 criteria provided, single submitter clinical testing

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