ClinVar Miner

Submissions for variant NM_000093.4(COL5A1):c.598G>A (p.Asp200Asn) (rs142890619)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000619239 SCV000738568 uncertain significance Cardiovascular phenotype 2017-06-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000196539 SCV000249873 uncertain significance not specified 2017-08-24 criteria provided, single submitter clinical testing The D200N variant in the COL5A1 gene has not been published as a mutation or reported as a benign polymorphism to our knowledge. The D200N variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, but was observed in 1/1006 alleles (0.1%) from individuals of European ancestry in the 1000 Genomes Project. The D200N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties, and occurs at a position that is conserved across species. Consequently, in silico analysis is inconsistent in its predictions as to whether this variant is damaging to the protein structure/function. No missense mutations in nearby residues have been reported in association with classic-type EDS, and the majority of mutations in the COL5A1 gene are truncating changes that result in a nonfunctional COL5A1 allele (Malfait F et al., 2011).Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. This variant was found in COL5A1,TAAD
Invitae RCV000230081 SCV000283505 uncertain significance Ehlers-Danlos syndrome, classic type 2018-10-23 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 200 of the COL5A1 protein (p.Asp200Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs142890619, ExAC 0.06%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with COL5A1-related disease. ClinVar contains an entry for this variant (Variation ID: 213015). 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, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
PreventionGenetics RCV000196539 SCV000302246 likely benign not specified criteria provided, single submitter clinical testing

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