ClinVar Miner

Submissions for variant NM_000393.5(COL5A2):c.3178C>T (p.Arg1060Trp) (rs374549843)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000197533 SCV000249977 uncertain significance not provided 2012-11-29 criteria provided, single submitter clinical testing TAAD is a genetically heterogeneous disorder characterized by aortic dilatation, aneurysms, dissections and/or aneurysms of other major arteries. Approximately 4% of patients with autosomal dominant Ehlers-Danlos syndrome, classic type, have been reported to have a mutation in the COL5A2 gene (Malfait F et al., 2011). The Arg1060Trp variant in the COL5A2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Arg1060Trp results in a non-conservative amino acid substitution of positively charged Arginine with a non-polar Tryptophan at a position that is conserved across species. In silico analysis predicts Arg1060Trp is probably damaging to the protein structure/function. Nevertheless, no mutations in nearby codons have been reported in association with Ehlers Danlos syndrome. The NHLBI ESP Exome Variant Server reports Arg1060Trp was observed in 2/8,598 alleles from individuals of European background. With the clinical and molecular information available at this time, we cannot definitively determine if Arg1060Trp is a disease-causing mutation or a rare benign variant. This variant was found in TAAD.
Illumina Clinical Services Laboratory,Illumina RCV000294359 SCV000425628 uncertain significance Ehlers-Danlos syndrome, type 7A 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000535369 SCV000631593 uncertain significance Ehlers-Danlos syndrome, classic type 2019-10-25 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 1060 of the COL5A2 protein (p.Arg1060Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs374549843, ExAC 0.009%) but has not been reported in the literature in individuals with a COL5A2-related disease. ClinVar contains an entry for this variant (Variation ID: 213114). 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 disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000617776 SCV000738690 uncertain significance Cardiovascular phenotype 2016-07-28 criteria provided, single submitter clinical testing Insufficient evidence
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001197291 SCV001367941 uncertain significance Epicanthus; Inguinal hernia; Hypotelorism; Kyphoscoliosis; Almond-shaped palpebral fissure; Anteverted nares; Clinodactyly of the 5th finger; Frontal bossing; Premature birth; Protruding ear; Short 5th finger; Short philtrum; Synophrys; Low anterior hairline; Pectus carinatum; Hypertrophic cardiomyopathy; Phimosis; Coarse hair; Bilateral single transverse palmar creases; Prominent eyelashes; Neonatal asphyxia 2019-03-01 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence on this varinat's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3. This variant was detected in heterozygous state.

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