ClinVar Miner

Submissions for variant NM_004612.4(TGFBR1):c.52GCG[10] (p.Ala26dup)

dbSNP: rs11466445
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001579589 SCV000250867 likely benign not provided 2021-01-08 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 29768367, 30487145, 11746979, 10582683, 16204663)
Invitae RCV000526310 SCV000658857 likely benign Familial thoracic aortic aneurysm and aortic dissection 2021-12-13 criteria provided, single submitter clinical testing
Eurofins NTD LLC (GA) RCV000195794 SCV000702913 likely benign not specified 2016-11-02 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000526310 SCV001333555 likely benign Familial thoracic aortic aneurysm and aortic dissection 2019-01-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000195794 SCV001363334 likely benign not specified 2022-07-25 criteria provided, single submitter clinical testing Variant summary: TGFBR1 c.76_78dupGCG (p.Ala26dup) causes the insertion of 3 nucleotides into exon 1 of the TGFBR1 mRNA that results in an in-frame insertion of an Alanine residue into a polyalanine stretch (consisting of 9 Alanines) in the encoded protein sequence. The variant is also described as TGFBR1*10A in the literature. The variant allele was found at a frequency of 0.00067 in 26720 control chromosomes (gnomAD). The observed variant frequency is approximately 360-fold of the estimated maximal expected allele frequency for a pathogenic variant in TGFBR1 causing Loeys-Dietz Syndrome phenotype (1.9e-06), strongly suggesting that the variant is benign. Though these data must be evaluated with caution, as this region is indicated to be of poor quality in the gnomAD database. The variant, c.76_78dupGCG, has been reported in the literature in an individual with suspected Loeys-Dietz Syndrome (example, Seo_2018), but was also found in healthy controls (Samowitz_2001, Rego_2018). These reports therefore do not provide unequivocal conclusions about association of the variant with Loeys-Dietz Syndrome. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated no damaging effect for this variant on either targeting to or translocation across the endoplasmic reticulum membrane as well as no impact on TGF-beta signaling (example, Pasche_1999, Pasche_2005). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with a majority consensus as lilely benign (n=5) (VUS, n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Genetic Services Laboratory,University of Chicago RCV000195794 SCV002067555 uncertain significance not specified 2019-04-17 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV001579589 SCV002545702 likely benign not provided 2022-09-01 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV001579589 SCV001807819 likely benign not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV001579589 SCV001956560 likely benign not provided no assertion criteria provided clinical testing

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