ClinVar Miner

Submissions for variant NM_000090.3(COL3A1):c.2498A>G (p.Lys833Arg) (rs371344739)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766809 SCV000233334 uncertain significance not provided 2018-07-11 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the COL3A1 gene. The K833R variant has not been published as pathogenic or been reported as benign to our knowledge. The K833R variant is observed at a frequency of 18/72356 alleles (0.02%) in individuals of European (non-Finnish) background in large population cohorts (Lek et al., 2016). The K833R variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Lastly, though located in the triple helical region of COL3A1, this variant does not affect a glycine residue in a Gly-X-Y motif, where the majority of pathogenic missense variants occur (Stenson et al., 2014; Symoens et al., 2012). Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000463723 SCV000541816 uncertain significance Ehlers-Danlos syndrome, type 4 2019-12-29 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 833 of the COL3A1 protein (p.Lys833Arg). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and arginine. This variant is present in population databases (rs371344739, ExAC 0.03%). This variant has not been reported in the literature in individuals with a COL3A1-related disease. ClinVar contains an entry for this variant (Variation ID: 199701). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Unknown"; Align-GVGD: "Class C0". The arginine 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, this variant has uncertain impact on COL3A1 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000181058 SCV000603137 uncertain significance not specified 2016-10-14 criteria provided, single submitter clinical testing
Ambry Genetics RCV000620126 SCV000738534 uncertain significance Cardiovascular phenotype 2017-07-27 criteria provided, single submitter clinical testing The p.K833R variant (also known as c.2498A>G), located in coding exon 36 of the COL3A1 gene, results from an A to G substitution at nucleotide position 2498. The lysine at codon 833 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species, and arginine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics,Fulgent Genetics RCV000463723 SCV000896915 uncertain significance Ehlers-Danlos syndrome, type 4 2018-10-31 criteria provided, single submitter clinical testing
Color Health, Inc RCV000778018 SCV000914128 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2019-11-05 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000181058 SCV001363407 likely benign not specified 2019-03-18 criteria provided, single submitter clinical testing Variant summary: COL3A1 c.2498A>G (p.Lys833Arg) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 180198 control chromosomes. The observed variant frequency is approximately 102 fold of the estimated maximal expected allele frequency for a pathogenic variant in COL3A1 causing Aortopathy phenotype (1.3e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.2498A>G in individuals affected with Aortopathy/Ehlers-Danlos syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Baylor Genetics RCV000463723 SCV001522854 uncertain significance Ehlers-Danlos syndrome, type 4 2019-11-21 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

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