Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000198438 | SCV000250874 | uncertain significance | not provided | 2013-11-15 | criteria provided, single submitter | clinical testing | p.Leu196Phe (CTT>TTT): c.586 C>T in exon 4 of the TGFBR1 gene (NM_004612.2) The Leu196Phe variant in the TGFBR1 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. The Leu196Phe variant is a conservative amino substitution as these residues share similar properties, and are least likely to impact secondary structure. However, the Leu196 residue is conserved across species. In silico analysis predicts Leu196Phe is probably damaging to the protein structure/function. Mutations in a nearby residue (Thr200Ile, Thr200Pro) have been reported in association with Loeys-Dietz syndrome, further supporting the functional importance of this region of the protein. Furthermore, the Leu196Phe variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. With the clinical and molecular information available at this time, we cannot definitively determine if Leu196Phe is a disease-causing mutation or a rare benign variant. This variant was found in TAAD |
| Victorian Clinical Genetics Services, |
RCV002272171 | SCV002557723 | likely pathogenic | Loeys-Dietz syndrome 1 | 2024-10-10 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with multiple self-healing squamous epithelioma (MSSE) (MIM#132800) (PMID: 21358634). Dominant negative is a suspected mechanism of disease in this gene and has been associated with Loeys–Dietz syndrome (LDS) (MIM#609192) (PMID: 29706644). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 32339686). (I) 0200 - Variant is predicted to result in a missense amino acid change from leucine to phenylalanine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (v2, v3 and v4). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated GS motif (Uniprot). (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. A different variant in the same codon resulting in a change to an arginine has been reported as a VUS (ClinVar). (I) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. This variant has been reported in another family tested at VCGS, with a history of aortic dilatation and aortic dissection. This variant has also been reported as a VUS in an individual with history of aortic dissection, lung collapse, pectus excavatum, and periumbilical hernia (ClinVar; GeneDx personal communication). (SP) 0902 - This variant has moderate evidence for segregation with disease. The variant segregates with disease in this individual's family and one other family tested at VCGS. (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |
| Labcorp Genetics |
RCV002515370 | SCV003308088 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection | 2022-02-01 | 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 213870). This variant has not been reported in the literature in individuals affected with TGFBR1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 196 of the TGFBR1 protein (p.Leu196Phe). |
| Molecular Genetics, |
RCV002515370 | SCV005900425 | likely pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2024-05-02 | criteria provided, single submitter | clinical testing | This sequence change in TGFBR1 is predicted to replace leucine with phenylalanine at codon 196, p.(Leu196Phe). The leucine residue is highly conserved (100 vertebrates, Multiz Alignments), and is located in the GS motif. There is a small physicochemical difference between leucine and phenylalanine. This variant is absent from the population database gnomAD v4.1. This variant has been reported in at least two probands with a history of aortic dilatation and aortic dissection (ClinVar: SCV002557723.1, SCV000250874.10). The variant cosegregates with aortopathy in at least two families (ClinVar: SCV002557723.1; Royal Melbourne Hospital). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.83). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PP1_Strong, PS4_Supporting, PM2_Supporting, PP3. |