ClinVar Miner

Submissions for variant NM_000090.3(COL3A1):c.3654G>T (p.Pro1218=) (rs35759441)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181063 SCV000233339 benign not specified 2014-10-20 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
PreventionGenetics,PreventionGenetics RCV000181063 SCV000302047 benign not specified criteria provided, single submitter clinical testing
Ambry Genetics RCV000253866 SCV000319186 benign Cardiovascular phenotype 2014-06-03 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
Invitae RCV000757113 SCV000554718 benign Ehlers-Danlos syndrome, type 4 2019-12-31 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000181063 SCV000885232 benign not specified 2019-03-08 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770603 SCV000902053 benign Familial thoracic aortic aneurysm and aortic dissection 2016-06-24 criteria provided, single submitter clinical testing
Color RCV000770603 SCV000903388 benign Familial thoracic aortic aneurysm and aortic dissection 2018-03-08 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000181063 SCV000917254 benign not specified 2018-10-16 criteria provided, single submitter clinical testing Variant summary: COL3A1 c.3654G>T alters a non-conserved nucleotide resulting in a synonymous change. 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 0.0014 in 277504 control chromosomes in the gnomAD database and publications, including 6 homozygotes. The observed variant frequency is approximately 1100-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.3654G>T in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign.
Illumina Clinical Services Laboratory,Illumina RCV000757113 SCV001299202 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

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