ClinVar Miner

Submissions for variant NM_001278074.1(COL5A1):c.2947G>A (p.Glu983Lys) (rs146348246)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000197473 SCV000249808 uncertain significance not provided 2014-05-14 criteria provided, single submitter clinical testing The E983K variant in the COL5A1 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. E983K results in a non-conservative amino acid substitution of a negatively charged Glutamic Acid with a positively charged Lysine at a position that is completely conserved across species. Consequently, in silico analysis predicts E983K is damaging to the protein structure/function. The E983K 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, indicating it is not a common benign variant in these populations. However, missense mutations in nearby residues have not been reported in association with classic-type EDS and the majority of mutations in the COL5A1 gene are truncating changes, or missense mutations in which a Glycine residue is replaced by any other amino acid in a region of the protein that contains numerous Gly-X-Y repeats (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
Fulgent Genetics,Fulgent Genetics RCV000766049 SCV000897499 uncertain significance Ehlers-Danlos syndrome, classic type 2018-10-31 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000197473 SCV000927499 uncertain significance not provided 2017-12-21 criteria provided, single submitter clinical testing
Invitae RCV000766049 SCV000952385 uncertain significance Ehlers-Danlos syndrome, classic type 2018-07-02 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 983 of the COL5A1 protein (p.Glu983Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with COL5A1-related disease. ClinVar contains an entry for this variant (Variation ID: 212952). 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 and their clinical significance is uncertain. 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.

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