ClinVar Miner

Submissions for variant NM_000090.3(COL3A1):c.4021G>A (p.Gly1341Ser) (rs140646380)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000726900 SCV000233391 uncertain significance not provided 2021-02-25 criteria provided, single submitter clinical testing Has not been published in association with connective tissue disease to our knowledge; Not located in the triple helical region, where the majority of pathogenic missense variants occur (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar (ClinVar Variant ID#199746; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 25356970, 20518783, 23688910, 11577371, 30379966, 28742248, 25758994, 26666608, 24922459, 21637106, 19455184, 10706896, 9712532, 9557891, 7833919, 27153395)
Ambry Genetics RCV000190743 SCV000244184 uncertain significance Inborn genetic diseases 2014-08-11 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000351166 SCV000425549 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000726900 SCV000703976 uncertain significance not provided 2017-01-05 criteria provided, single submitter clinical testing
Invitae RCV000351166 SCV000756069 likely benign Ehlers-Danlos syndrome, type 4 2019-12-31 criteria provided, single submitter clinical testing
Color Health, Inc RCV000771816 SCV000904519 likely benign Familial thoracic aortic aneurysm and aortic dissection 2018-05-21 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001194125 SCV001363415 likely benign not specified 2019-04-29 criteria provided, single submitter clinical testing Variant summary: COL3A1 c.4021G>A (p.Gly1341Ser) results in a non-conservative amino acid change located in the Fibrillar collagen, C-terminal domain (IPR000885) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00023 in 251334 control chromosomes (gnomAD). The observed variant frequency is approximately 181 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. c.4021G>A has been reported in the literature in individuals affected with bipolar disorder or hereditary cancer (Maaser_2018, Maxwell_2016). These reports do not provide unequivocal conclusions about association of the variant with Aortopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as likely benign (2x) and twice as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.

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