Submissions for variant NM_004612.4(TGFBR1):c.1040G>C (p.Cys347Ser)

gnomAD frequency: 0.00005  dbSNP: rs113786548

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001177119	SCV001341262	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-09-20	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with serine at codon 347 of the TGFBR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with TGFBR1-related disorders in the literature. This variant has been identified in 5/282394 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.
Ambry Genetics	RCV001177119	SCV002699405	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2024-05-26	criteria provided, single submitter	clinical testing	The p.C347S variant (also known as c.1040G>C), located in coding exon 6 of the TGFBR1 gene, results from a G to C substitution at nucleotide position 1040. The cysteine at codon 347 is replaced by serine, an amino acid with dissimilar properties, and is located in the protein kinase domain. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002483962	SCV002789430	uncertain significance	Loeys-Dietz syndrome 1; Multiple self-healing squamous epithelioma	2021-09-01	criteria provided, single submitter	clinical testing
GeneDx	RCV003314668	SCV004014607	uncertain significance	not provided	2023-07-14	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV001177119	SCV004392723	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-09-04	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. This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 347 of the TGFBR1 protein (p.Cys347Ser). This variant is present in population databases (rs113786548, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with TGFBR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 919136). 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 TGFBR1 protein function.
All of Us Research Program, National Institutes of Health	RCV004006361	SCV004840413	uncertain significance	Loeys-Dietz syndrome	2023-12-18	criteria provided, single submitter	clinical testing	Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the cytoplasmic, protein kinase domain of the TGFBR1 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 4/276704 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively.