ClinVar Miner

Submissions for variant NM_000090.3(COL3A1):c.1856C>T (p.Pro619Leu) (rs373838193)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000319906 SCV000425520 likely benign Ehlers-Danlos syndrome, type 4 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
GeneDx RCV000523302 SCV000617055 uncertain significance not provided 2017-11-08 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the COL3A1 gene. The P619L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant has been identified in one other unrelated individual referred for Marfan/TAAD genetic testing at GeneDx; however, segregation data for this individual is absent. P619L was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in an external variant database, indicating it is not a common benign variant in these populations. The P619L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. However, although the P619L variant occurs within a in the triple helical region of the COL3A1 gene, it does not affect a Glycine residue in a Gly-X-Y motif, where the majority of pathogenic missense variants occur (Stenson et al., 2014; Symoens et al., 2012). Furthermore, in silico analysis is inconsistent in its predictions as to whether or not P619L is damaging to the protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Invitae RCV000319906 SCV000631634 uncertain significance Ehlers-Danlos syndrome, type 4 2018-11-27 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 619 of the COL3A1 protein (p.Pro619Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs373838193, ExAC 0.01%). This variant has not been reported in the literature in individuals with a COL3A1-related disease. ClinVar contains an entry for this variant (Variation ID: 333057). 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, this variant has uncertain impact on COL3A1 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000621849 SCV000738552 uncertain significance Cardiovascular phenotype 2017-05-10 criteria provided, single submitter clinical testing Insufficient evidence
Color RCV001189166 SCV001356397 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2019-08-11 criteria provided, single submitter clinical testing
CSER _CC_NCGL, University of Washington RCV000319906 SCV000503543 uncertain significance Ehlers-Danlos syndrome, type 4 2016-08-01 no assertion criteria provided research Found in patient having exome sequencing for an unrelated indication. No known history of Ehlers-Danlos syndrome, type IV

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