ClinVar Miner

Submissions for variant NM_004612.4(TGFBR1):c.415A>G (p.Ile139Val) (rs148176750)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000619699 SCV000739750 likely benign Cardiovascular phenotype 2017-01-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Subpopulation frequency in support of benign classification,In silico models in agreement (benign)
Center for Human Genetics, Inc RCV000229273 SCV000782356 likely benign Thoracic aortic aneurysm and aortic dissection 2016-11-01 criteria provided, single submitter clinical testing
GeneDx RCV000766901 SCV000514886 uncertain significance not provided 2017-01-13 criteria provided, single submitter clinical testing The I139V variant in the TGFBR1 gene has been reported as a variant of uncertain significance in one Caucasianindividual with MASS phenotype (Lerner-Ellis et al., 2014). In addition, this variant is classified as a variant ofuncertain significance in ClinVar by two external clinical laboratories (SCV000204110.3; SCV000288620.2;Landrum et al., 2016). Although this variant has been identified in two other probands referred to GeneDx for Marfansyndrome/TAAD testing, one individual harbored a co-occurring cardiogenetic variant and segregation studies forI139V were not performed. This substitution occurs at a position where only amino acids with similar properties toIsoleucine are tolerated across species. However, the I139V variant is a conservative amino acid substitution, which isnot likely to impact secondary protein structure as these residues share similar properties. Furthermore,Valine isobserved as the wild type residue in multiple species, and two of three in silico models predicts this variant likelydoes not alter the protein structure/function. Finally, the I139V variant is observed in 22/66712 (0.033%) alleles fromindividuals of European Non-Finnish ancestry in the ExAC dataset (Lek et al., 2016; 1000 Genomes Consortium etal., 2015; Exome Variant Server). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Illumina Clinical Services Laboratory,Illumina RCV000229273 SCV000475612 likely benign Thoracic aortic aneurysm and aortic dissection 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000328066 SCV000475613 likely benign Loeys-Dietz syndrome 1 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000384899 SCV000475614 likely benign Loeys-Dietz syndrome 2016-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000154441 SCV000918307 likely benign not specified 2017-10-13 criteria provided, single submitter clinical testing Variant summary: The c.415A>G (p.Ile139Val) in TGFBR1 gene is a missense change that involves the alteration of a non- conserved nucleotide and 5/4 in silico tools predict benign outcome. The variant was observed in the control datasets of the ExAC and gnomAD at a frequency of 0.00025 (24/121346 and 62/245812 chrs tested, including 1 homozygote). The observed frequency exceeds the maximal expected allele frequency for a pathogenic variant in this gene (0.000002). The variant has been identified in 1 individual with suspected MSF/LDS or TAAD, without strong evidence for causality (Lerner-Ellis_2014). In addition, one clinical laboratory reports co-occurrence of this variant with unspecified pathogenic cardiogenetic variant with disclosure that segregation analysis was not performed. Although several reputable databases/diagnostic centers classified the variant of interest as VUS/Likely Benign, by applying ACMG rules the variant was classified as Likely Benign.
Invitae RCV000229273 SCV000288620 likely benign Thoracic aortic aneurysm and aortic dissection 2017-05-26 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000154441 SCV000204110 uncertain significance not specified 2016-02-11 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory

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