ClinVar Miner

Submissions for variant NM_001278074.1(COL5A1):c.3868G>A (p.Ala1290Thr) (rs863223451)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000195614 SCV000249824 uncertain significance not provided 2014-08-13 criteria provided, single submitter clinical testing The A1290T variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The A1290T variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The A1290T 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. This substitution occurs at a position that is conserved in mammals. Moreover, a missense mutations in a nearby residue (E1292K) has been reported in association with EDS, supporting the functional importance of this region of the protein. Nevertheless, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Based on the currently available clinical and molecular information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant.This variant was found in COL5A1,TAAD
Ambry Genetics RCV000254347 SCV000319896 uncertain significance Cardiovascular phenotype 2015-07-12 criteria provided, single submitter clinical testing Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (benign);Insufficient or conflicting evidence
Invitae RCV000472036 SCV000549002 uncertain significance Ehlers-Danlos syndrome, classic type 2016-05-22 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 1290 of the COL5A1 protein (p.Ala1290Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a COL5A1-related disease. ClinVar contains an entry for this variant (Variation ID: 212967). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes 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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