Submissions for variant NM_004612.4(TGFBR1):c.973+1G>A

dbSNP: rs863223818

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170914	SCV001333560	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2019-02-26	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV003993884	SCV004812334	likely pathogenic	Loeys-Dietz syndrome	2024-04-11	criteria provided, single submitter	clinical testing	This sequence change in TGFBR1 occurs within the canonical splice donor site of intron 5. RT-PCR assays on patient cells and mini-gene assays demonstrated loss of the exon 5 donor site resulting in two in-frame splicing events within the serine-threonine kinase domain; exon 5 skipping and cryptic donor activation leading to a 9 bp deletion (r.[806_973del, 965_973del] p.[Asp269_Gln324del, Thr323_Gly325del]; PMID: 29706644). This variant is absent from the population database gnomAD v2.1 and v3.1. This variant has been reported in at least two probands with phenotypes consistent with TGFBR1-related aortopathy (PMID: 29706644; Royal Melbourne Hospital). The variant has been reported to segregate in three affected family members from a single family (PMID: 29706644). An in vitro assay in HEK293T cells showed a reduction in luciferase activity due to the complete deletion of exon 5 and the 9 bp deletion, suggestive of reduced TGFBR1 protein activity. This finding suggests that this variant impacts protein function (PMID: 29706644). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PVS1_Moderate, PM2_Supporting, PP1, PS3_Supporting, PS4_Supporting
GeneDx	RCV000196022	SCV000250887	uncertain significance	not provided	2017-05-25	flagged submission	clinical testing	The c.973+1 G>A splice site variant has not been reported as a pathogenic variant or as a benign polymorphism to our knowledge. This variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The c.973+1 G>A variant destroys the canonical splice donor site in intron 5 and is likely to result in aberrant splicing. In the absence of functional/mRNA studies, however, the in-vitro consequence of this variant cannot be precisely determined. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.