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

dbSNP: rs11466445

Total submissions: 11

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	2024-02-01	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	2023-06-01	criteria provided, single submitter	clinical testing	TGFBR1: BS1
Ambry Genetics	RCV000526310	SCV002673739	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2020-09-08	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
PreventionGenetics, part of Exact Sciences	RCV003937726	SCV004747475	likely benign	TGFBR1-related condition	2020-03-11	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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