ClinVar Miner

Submissions for variant NM_000393.5(COL5A2):c.2291C>G (p.Pro764Arg) (rs150260969)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000198963 SCV000249969 uncertain significance not specified 2017-04-20 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the COL5A2 gene. The P764R variant has not been published as pathogenic or been reported as benign to our knowledge. However, it is classified as a variant of uncertain significance in ClinVar by two other clinical laboratories (ClinVar SCV000319507.1, SCV000547891.1; Landrum et al., 2016). The P764R 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 across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, this variant has been observed in 58/66,568 (0.09%) alleles from individuals of Non-Finnish European ancestry in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Additionally, this variant does not affect a Glycine residue in a Gly-X-Y motif in the triple helical region of the COL5A2 gene, where the majority of pathogenic missense variants occur (Stenson et al., 2014; Symoens et al., 2012). However, in contrast to several other collagen genes, relatively few pathogenic Glycine substitutions have been reported in COL5A2 in association with Ehlers-Danlos syndrome. Most pathogenic variants in COL5A2 are in-frame splice site changes that cause exon skipping (Symoens et al., 2012).
Ambry Genetics RCV000242357 SCV000319507 benign Cardiovascular phenotype 2017-01-24 criteria provided, single submitter clinical testing General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
Illumina Clinical Services Laboratory,Illumina RCV000387034 SCV000425644 likely benign Ehlers-Danlos syndrome, type 7A 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000467216 SCV000547891 benign Ehlers-Danlos syndrome, classic type 2019-12-31 criteria provided, single submitter clinical testing
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000680515 SCV000807901 uncertain significance Connective tissue disease 2018-06-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001137175 SCV001297090 likely benign Ehlers-Danlos syndrome classic type 2 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.

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