Submissions for variant NM_004612.4(TGFBR1):c.1285T>C (p.Tyr429His)

gnomAD frequency: 0.00007  dbSNP: rs201745016

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000762568	SCV000892900	uncertain significance	not provided	2023-06-01	criteria provided, single submitter	clinical testing
Invitae	RCV000802300	SCV000942125	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 429 of the TGFBR1 protein (p.Tyr429His). This variant is present in population databases (rs201745016, gnomAD 0.008%). This missense change has been observed in individual(s) with clinical features of nonsyndromic thoracic aortic aneurysms and aortic dissections (TAAD) and/or fibromuscular dysplasia (PMID: 23064905; Invitae). ClinVar contains an entry for this variant (Variation ID: 624363). 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 not expected to disrupt TGFBR1 protein function with a negative predictive value of 80%. 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.
Color Diagnostics, LLC DBA Color Health	RCV000802300	SCV001353211	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-02-16	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with histidine at codon 429 of the TGFBR1 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 not been reported in individuals affected with TGFBR1-related disorders in the literature. This variant has been identified in 7/282220 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.
GeneDx	RCV000762568	SCV001824138	uncertain significance	not provided	2021-01-28	criteria provided, single submitter	clinical testing	Reported in one individual diagnosed with medial fibroplasia who had a history of multi-vessel dissection involving the internal carotid and vertebral arteries, ascending aortic aneurysm, marked tortuosity of the descending aorta, no gross craniofacial abnormalities, and a unifid uvula with normal appearing palate (Poloskey et al., 2012); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 23064905)
Ambry Genetics	RCV000802300	SCV002688975	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2021-04-27	criteria provided, single submitter	clinical testing	The p.Y429H variant (also known as c.1285T>C), located in coding exon 8 of the TGFBR1 gene, results from a T to C substitution at nucleotide position 1285. The tyrosine at codon 429 is replaced by histidine, an amino acid with similar properties. The alteration has been reported in a subject with a history of medial fibroplasia, multi-vessel dissection involving the internal carotid and vertebral arteries, and ectasia of the ascending aorta (Poloskey SL et al. Vasc Med, 2012 Dec;17:371-8). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470973	SCV002766818	uncertain significance	Loeys-Dietz syndrome 1	2022-03-31	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene. In addition, missense variants have been postulated to exert a dominant negative effect. Both mechanisms are reported in association with Loeys-Dietz syndrome (MIM#609192) (PMID: 30701076). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. There is considerable variability in the phenotype, from mild features to severe systemic abnormalities and also an overlap in the manifestations with Marfan syndrome, including increased risk of ascending aortic aneurysm and aortic dissection, abnormally long limbs and fingers (PMID: 32339686). (I) 0200 - Variant is predicted to result in a missense amino acid change from tyrosine to histidine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2 & v3) <0.001 for a dominant condition (15 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated protein kinase domain (DECIPHER). (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. p.(Tyr429Cys) was identified in a prospective Japanese cohort (PMID: 29192238). (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. It has been reported in an individual with medial fibroplasia who had a history of multi-vessel dissection involving the internal carotid and vertebral arteries and aneurysm of the ascending aorta; the variant was regarded as VUS (PMID: 23064905). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
PreventionGenetics, part of Exact Sciences	RCV003928265	SCV004740519	uncertain significance	TGFBR1-related condition	2023-12-08	criteria provided, single submitter	clinical testing	The TGFBR1 c.1285T>C variant is predicted to result in the amino acid substitution p.Tyr429His. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0080% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-101909965-T-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.