ClinVar Miner

Submissions for variant NM_000090.3(COL3A1):c.3818A>G (p.Lys1273Arg) (rs144614075)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000244720 SCV000319224 uncertain significance Cardiovascular phenotype 2013-12-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000771822 SCV000904527 uncertain significance Thoracic aortic aneurysm and aortic dissection 2018-08-28 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the C-terminal propeptide domain of the COL3A1 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on 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 33/275664 chromosomes (33/125272 non-Finnish European chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Although this variant frequency is relatively high for COL3A1-associated diseases, available evidence is insufficient to rule out the pathogenicity of this variant conclusively.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000725829 SCV000339677 uncertain significance not provided 2016-03-03 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515270 SCV000611385 uncertain significance Ehlers-Danlos syndrome, type 4; Ehlers-Danlos syndrome, type 3 2017-05-23 criteria provided, single submitter clinical testing
GeneDx RCV000725829 SCV000233388 uncertain significance not provided 2018-03-21 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the COL3A1 gene. The K1273R variant has been reported previously in one individual with vascular Ehlers-Danlos syndrome (vEDS) and in two unrelated patients with arterial aneurysms (Ong et al., 2010; Frank et al., 2015). K1273R was also reported as a variant of uncertain significance in a patient with familial thoracic aortic aneurysm (TAA) (Schubert et al., 2016). This variant has been observed in 10/65,996 (0.01%) Non-Finnish European alleles in the Exome Aggregation Consortium data-set (Lek et al., 2016). Additionally, the K1273R variant has been seen in multiple individuals referred for Marfan/TAAD testing at GeneDx; however, segregation data is limited thus far due to insufficient participation by informative family members.The K1273R variant is a conservative amino acid substitution which is not likely to impact secondary protein structure, as these residues share similar properties. This substitution occurs at a position that is not conserved across species, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Notably, the K1273R variant does not affect a Glycine residue in a Gly-X-Y motif in the triple helical region of the COL3A1 gene, where the majority of pathogenic missense variants occur (Stenson et al., 2014; Symoens et al., 2012).
Invitae RCV000204516 SCV000262437 likely benign Ehlers-Danlos syndrome, type 4 2018-01-03 criteria provided, single submitter clinical testing

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