ClinVar Miner

Submissions for variant NM_003242.6(TGFBR2):c.1643C>T (p.Ser548Leu)

gnomAD frequency: 0.00001  dbSNP: rs755070814
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000464975 SCV000548117 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2023-07-28 criteria provided, single submitter clinical testing In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TGFBR2 protein function. ClinVar contains an entry for this variant (Variation ID: 408441). This variant is also known as c.1718C>T; p.Ser573Leu. This missense change has been observed in individual(s) with TGFBR2-related conditions (PMID: 32897753). This variant is present in population databases (rs755070814, gnomAD 0.01%). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 548 of the TGFBR2 protein (p.Ser548Leu).
Color Diagnostics, LLC DBA Color Health RCV000464975 SCV001346224 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2023-05-18 criteria provided, single submitter clinical testing This missense variant replaces serine with leucine at codon 548 of the TGFBR2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with spontaneous coronary artery dissection and renal fibromuscular dysplasia (PMID: 32897753). This variant has been identified in 4/251188 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001420946 SCV001623411 uncertain significance not specified 2021-05-03 criteria provided, single submitter clinical testing Variant summary: TGFBR2 c.1643C>T (p.Ser548Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251188 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1643C>T in individuals affected with Loeys-Dietz Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx RCV001555666 SCV001777118 uncertain significance not provided 2021-08-06 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Fulgent Genetics, Fulgent Genetics RCV002480400 SCV002790404 uncertain significance Loeys-Dietz syndrome 2; Malignant tumor of esophagus; Colorectal cancer, hereditary nonpolyposis, type 6 2021-09-07 criteria provided, single submitter clinical testing

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