Submissions for variant NM_004612.4(TGFBR1):c.207C>T (p.Ser69=)

gnomAD frequency: 0.00019  dbSNP: rs145033378

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000199569	SCV000250869	uncertain significance	not provided	2021-05-05	criteria provided, single submitter	clinical testing	In-silico analysis is inconclusive as to whether the variant alters gene splicing; in the absence of RNA/functional studies, the actual effect of this sequence change is unknown; Reported as likely benign by other clinical laboratories in ClinVar but additional evidence is not available (ClinVar Variant ID# 213865; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 23142374)
Invitae	RCV000231583	SCV000288618	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2024-01-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000231583	SCV000739740	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2019-01-18	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Diagnostics, LLC DBA Color Health	RCV000231583	SCV000913783	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2018-05-29	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000199569	SCV001249912	likely benign	not provided	2023-12-01	criteria provided, single submitter	clinical testing	TGFBR1: BP4, BP7
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000199569	SCV002506016	uncertain significance	not provided	2022-01-28	criteria provided, single submitter	clinical testing	The TGFBR1 c.207C>T; p.Ser69= variant (rs145033378) is reported in the literature in an individual referred for genetic testing for thoracic aortic aneurysms and dissections, though its clinical significance was not demonstrated (Kathiravel 2013). This variant is also reported in ClinVar (Variation ID: 213865) and found in the Latino population with an overall allele frequency of 0.0565% (20/35368 alleles) in the Genome Aggregation Database. This is a synonymous variant in a weakly conserved nucleotide, but computational analyses (Alamut v.2.11) predict that this variant may impact splicing by creating a novel cryptic donor splice site. However, RNA sequencing studies would be required to confirm an effect on splicing. Due to limited information, the clinical significance of the p.Ser69= variant is uncertain at this time. References: Kathiravel U et al. High-density oligonucleotide-based resequencing assay for mutations causing syndromic and non-syndromic forms of thoracic aortic aneurysms and dissections. Mol Cell Probes. 2013;27(2):103-108. PMID: 23142374.
PreventionGenetics, part of Exact Sciences	RCV003947627	SCV004764997	likely benign	TGFBR1-related condition	2020-04-15	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).