ClinVar Miner

Submissions for variant NM_000090.3(COL3A1):c.198A>G (p.Ile66Met) (rs372269408)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000248865 SCV000318667 likely benign Cardiovascular phenotype 2015-10-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (benign),Co-occurence with a mutation in another gene that clearly explains a proband's phenotype
Color RCV000772093 SCV000905128 uncertain significance Thoracic aortic aneurysm and aortic dissection 2018-04-20 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This variant is a missense variant located in the N-terminal propeptide domain of the COL3A1 protein. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 7/245544 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Invitae RCV000634706 SCV000756041 uncertain significance Ehlers-Danlos syndrome, type 4 2017-08-14 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with methionine at codon 66 of the COL3A1 protein (p.Ile66Met). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and methionine. This variant is present in population databases (rs372269408, ExAC 0.01%). This variant has not been reported in the literature in individuals with COL3A1-related disease. ClinVar contains an entry for this variant (Variation ID: 263619). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The methionine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.

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