Submissions for variant NM_004612.4(TGFBR1):c.934G>A (p.Gly312Ser)

gnomAD frequency: 0.00001  dbSNP: rs760079636

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000199247	SCV000250886	likely pathogenic	not provided	2023-08-14	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar as likely pathogenic and pathogenic (ClinVar Variant ID#213882; ClinVar); This variant is associated with the following publications: (PMID: 16799921, 31915033, 19542084, 26877057, 26848186, 27879313, 17061023, 30739908)
Blueprint Genetics	RCV000208245	SCV000264244	likely pathogenic	Loeys-Dietz syndrome	2015-04-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001187849	SCV000318188	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2019-12-02	criteria provided, single submitter	clinical testing	The p.G312S variant (also known as c.934G>A), located in coding exon 5 of the TGFBR1 gene, results from a G to A substitution at nucleotide position 934. The glycine at codon 312 is replaced by serine, an amino acid with similar properties. This variant has been detected in multiple individuals with clinical presentations of Loeys-Dietz syndrome (Singh KK et al. Hum. Mutat., 2006 Aug;27:770-7; Luo M et al. Clin. Chim. Acta, 2016 May;456:144-8). In addition, the variant was reported to segregate with the disease in two families (Teixidó-Tura G et al. Heart, 2016 Apr;102:626-32; Tran-Fadulu V et al. J. Med. Genet., 2009 Sep;46:607-13). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Internal structural analysis suggested that G312 resides in the protein kinase domain and this variant would disrupt the protein structure (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235118	SCV000918303	pathogenic	Familial aortopathy	2023-05-08	criteria provided, single submitter	clinical testing	Variant summary: TGFBR1 c.934G>A (p.Gly312Ser) results in a non-conservative amino acid change located in the protein kinase domain (IPR000719) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251070 control chromosomes (gnomAD). c.934G>A has been reported in the literature in multiple individuals affected with Aortopathy, including patients and families with Loeys-Dietz Syndrome and TAAD, with strong segregation data (e.g. Luo_2016, Singh_2006, Teixido-Tura_2016, Tran-Fadulu_2009). These data indicate that the variant is very likely to be associated with disease. Additionally, the Montalcino Aortic Consortium reports the variant in 14 patients from an international registry, and showed the variant to have significantly poorer survival without aortic event (dissection or surgery) compared to patients with any other TGFRB1 mutations (Jondeau_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27879313, 26877057, 16799921, 26848186, 19542084, 31915033). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=1)/likely pathogenic (n=5). Based on the evidence outlined above, the variant was classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001187849	SCV001354742	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2023-06-22	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 312 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 been reported in an individual affected with Marfan syndrome with a family history of thoracic aortic aneurysm and dissection (PMID: 16799921) and in over 15 individuals affected with thoracic aortic aneurysm and dissection, including three related individuals (PMID: 19542084, 27879313, 30739908). This variant has also been identified in four individuals affected with Loeys-Dietz syndrome (PMID: 26877057, 26848186, 31915033, 36237225). This variant has been identified in 1/251070 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Invitae	RCV001187849	SCV002240761	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2023-09-08	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 213882). This missense change has been observed in individuals with TGFBR1-related conditions (PMID: 16799921, 19542084, 26848186, 26877057, 30739908). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs760079636, gnomAD 0.004%). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 312 of the TGFBR1 protein (p.Gly312Ser).
Institute of Human Genetics, University of Leipzig Medical Center	RCV002255135	SCV002526699	likely pathogenic	Loeys-Dietz syndrome 1	2022-04-29	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PS4, PM2_SUP, PP3
CeGaT Center for Human Genetics Tuebingen	RCV000199247	SCV004010843	likely pathogenic	not provided	2023-04-01	criteria provided, single submitter	clinical testing	TGFBR1: PM1, PM2, PP3, PS4:Supporting