Submissions for variant NM_003239.5(TGFB3):c.293C>T (p.Ser98Leu)

gnomAD frequency: 0.00092  dbSNP: rs142047577

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172592	SCV000051423	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
Ambry Genetics	RCV001171232	SCV000320681	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2019-05-03	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.
Invitae	RCV002516570	SCV000561264	likely benign	Rienhoff syndrome	2024-01-29	criteria provided, single submitter	clinical testing
CSER _CC_NCGL, University of Washington	RCV000590908	SCV000700098	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2016-10-01	criteria provided, single submitter	research	Found in patient having exome sequencing for an unrelated indication. No known history of arrhythmogenic right ventricular dysplasia. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000624174	SCV000740385	uncertain significance	Left ventricular noncompaction	2016-11-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000172592	SCV000981249	likely benign	not provided	2021-06-18	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23861362, 31110529, 25351510, 28798025, 27535533, 26582918)
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852702	SCV000995416	likely benign	Hypertrophic cardiomyopathy	2017-10-02	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000172592	SCV001159455	likely benign	not provided	2021-10-07	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001171232	SCV001333935	benign	Familial thoracic aortic aneurysm and aortic dissection	2018-04-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001844066	SCV002103686	likely benign	not specified	2024-02-20	criteria provided, single submitter	clinical testing	Variant summary: TGFB3 c.293C>T (p.Ser98Leu) results in a non-conservative amino acid change located in the TGF-beta, propeptide domain (IPR001111) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00074 in 251496 control chromosomes in the gnomAD database, including 2 homozygotes. The observed variant frequency is approximately 119-fold of the estimated maximal expected allele frequency for a pathogenic variant in TGFB3 causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy phenotype (6.3e-06), strongly suggesting that the variant is benign. c93C>T has been reported in the literature in individuals affected with left ventricular hypertrabeculation and dilated cardiomyopathy (Miszalski-Jamka_2017, Kuhnisch_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. 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: 31568572, 28798025). ClinVar contains an entry for this variant (Variation ID: 192131). Based on the evidence outlined above, the variant was classified as likely benign.
Dept of Medical Biology, Uskudar University	RCV003318362	SCV004022093	benign	Long QT syndrome	2024-01-08	criteria provided, single submitter	research	Criteria: BS1, BS2
CeGaT Center for Human Genetics Tuebingen	RCV000172592	SCV004130136	benign	not provided	2024-06-01	criteria provided, single submitter	clinical testing	TGFB3: BP4, BS1, BS2
PreventionGenetics, part of Exact Sciences	RCV003975250	SCV004791526	likely benign	TGFB3-related disorder	2019-02-21	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).