Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
3billion | RCV002283457 | SCV002573242 | likely pathogenic | Loeys-Dietz syndrome 2 | 2022-09-01 | criteria provided, single submitter | clinical testing | The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.65; 3Cnet: 0.97). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with TGFBR2 -related disorder (ClinVar ID: VCV000155839 / PMID: 16928994). A different missense change at the same codon (p.Cys461Arg) has been reported to be associated with TGFBR2 -related disorder (ClinVar ID: VCV000393299 / PMID: 28344185). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. |
Ambry Genetics | RCV002515939 | SCV003558433 | likely pathogenic | Inborn genetic diseases | 2021-04-02 | criteria provided, single submitter | clinical testing | The c.1382G>A (p.C461Y) alteration is located in exon 5 (coding exon 5) of the TGFBR2 gene. This alteration results from a G to A substitution at nucleotide position 1382, causing the cysteine (C) at amino acid position 461 to be replaced by a tyrosine (Y). Based on data from the Genome Aggregation Database (gnomAD), the TGFBR2 c.1382G>A alteration was not observed, with coverage at this position. This alteration has been previously reported in individuals with Loeys-Dietz syndrome type I (Loeys, 2006). Using alternate nomenclature, this variant (p.C486Y, c.1457G>A) has also been reported de novo in a patient with an atrial septal defect (Jin, 2017). Another alteration affecting the same amino acid, p.C461R, was reported in a neonatal female patient with features consistent with Loeys-Dietz syndrome (Valenzuela, 2017). The p.C461 amino acid is conserved in available vertebrate species. The p.C461Y alteration is located in the kinase domain of TGFBR2. Based on internal structural analysis, this alteration is anticipated to result in a significant decrease in structural stability (Tebben, 2016; Zimmermann, 2017). Functional analysis in fibroblasts explanted from a patient with the p.C461Y alteration showed disruption of fibroblast transformation into myofibroblasts with TGF-B1 stimulation; however, the clinical relevance of those results is unclear (Inamoto, 2010). The in silico prediction for the p.C461Y alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic. |
Blueprint Genetics | RCV000143955 | SCV000188835 | likely pathogenic | Loeys-Dietz syndrome | 2013-11-26 | no assertion criteria provided | clinical testing |