ClinVar Miner

Submissions for variant NM_000090.3(COL3A1):c.217G>C (p.Asp73His) (rs200246388)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000252739 SCV000319286 uncertain significance Cardiovascular phenotype 2015-06-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Color RCV000771273 SCV000903418 uncertain significance Thoracic aortic aneurysm and aortic dissection 2018-10-19 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the N-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 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 35/276374 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
GeneDx RCV000520803 SCV000620150 uncertain significance not provided 2018-03-22 criteria provided, single submitter clinical testing The D73H variant of uncertain significance in the COL3A1 gene has not been published as pathogenic or been reported as benign to our knowledge. The D73H 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. Moreover, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Nevertheless, the D73H 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). Finally, this variant is observed in 24/30,778 (0.08%) South Asian alleles and 10/126,058 (0.08%) European (non-Finnish) alleles in large population cohorts (Lek et al., 2016), indicating it may be a rare benign variant. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Illumina Clinical Services Laboratory,Illumina RCV000264796 SCV000425496 likely benign Ehlers-Danlos syndrome, type 4 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000264796 SCV000541783 uncertain significance Ehlers-Danlos syndrome, type 4 2016-09-09 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with histidine at codon 73 of the COL3A1 protein (p.Asp73His). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and histidine. This variant is present in population databases (rs200246388, ExAC 0.08%) but has not been reported in the literature in individuals with a COL3A1-related disease. 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, this variant is a rare missense change with uncertain impact on protein function. It is not expected to cause disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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