Submissions for variant NM_003239.5(TGFB3):c.873G>A (p.Pro291=)

gnomAD frequency: 0.00010  dbSNP: rs370006165

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002518336	SCV000287914	likely benign	Rienhoff syndrome	2024-11-28	criteria provided, single submitter	clinical testing
GeneDx	RCV001579502	SCV000532589	likely benign	not provided	2020-06-01	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 29907982)
Ambry Genetics	RCV002311347	SCV000737736	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2023-08-28	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000435962	SCV000920304	likely benign	not specified	2018-02-20	criteria provided, single submitter	clinical testing	Variant summary: TGFB3 c.873G>A alters a non-conserved nucleotide resulting in a synonymous change. Computational tools predict that the variant may alter splicing. However, these predictions have yet to be confirmed by functional studies. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 19-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in TGFB3 causing Arrhythmia phenotype (0.002 vs 1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.873G>A in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely benign, and one laboratory classified the variant as uncertain significance. Based on the available evidence, the variant was classified as likely benign.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001579502	SCV001807485	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001579502	SCV001927864	uncertain significance	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003947772	SCV004759966	likely benign	TGFB3-related disorder	2023-09-28	no assertion criteria provided	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).