ClinVar Miner

Submissions for variant NM_000090.3(COL3A1):c.1509+7A>C (rs201740954)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000399574 SCV000425513 benign Ehlers-Danlos syndrome, type 4 2018-01-12 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Invitae RCV000399574 SCV000631627 benign Ehlers-Danlos syndrome, type 4 2019-12-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001192746 SCV001361056 benign not specified 2019-07-01 criteria provided, single submitter clinical testing Variant summary: COL3A1 c.1509+7A>C alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0013 in 251296 control chromosomes in the gnomAD database, including 6 homozygotes. The observed variant frequency is approximately 1028.27 fold of the estimated maximal expected allele frequency for a pathogenic variant in COL3A1 causing Aortopathy phenotype (1.3e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1509+7A>C in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.

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