ClinVar Miner

Submissions for variant NM_001849.3(COL6A2):c.1358G>A (p.Arg453His) (rs878854386)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Genetic Medicine Research,Children's National Medical Center RCV000234070 SCV000265801 uncertain significance not specified 2015-12-01 criteria provided, single submitter research
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000726521 SCV000345204 uncertain significance not provided 2017-12-07 criteria provided, single submitter clinical testing
GeneDx RCV000726521 SCV000617133 uncertain significance not provided 2015-09-04 criteria provided, single submitter clinical testing The R453H variant has not beenpublished as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. It was notobserved in approximately 5,500 individuals of European and African American ancestry in the NHLBI ExomeSequencing Project, indicating it is not a common benign variant in these populations. The R453H variant is aconservative amino acid substitution, which is not likely to impact secondary protein structure as theseresidues share similar properties. However, this substitution occurs at a position that is conserved acrossspecies, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging tothe protein structure/function.
Invitae RCV000685020 SCV000812489 uncertain significance Bethlem myopathy 1 2018-04-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 453 of the COL6A2 protein (p.Arg453His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported in an individual affected with limb-girdle muscular dystrophy, type unknown (PMID: 27854218). ClinVar contains an entry for this variant (Variation ID: 224685). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.

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