Submissions for variant NM_003238.6(TGFB2):c.356C>T (p.Pro119Leu)

gnomAD frequency: 0.00047  dbSNP: rs149533093

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000196866	SCV000250839	likely benign	not specified	2018-01-05	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Illumina Laboratory Services, Illumina	RCV000415640	SCV000354238	benign	Loeys-Dietz syndrome 4	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Invitae	RCV000415640	SCV000548101	likely benign	Loeys-Dietz syndrome 4	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000769556	SCV000739695	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2020-11-03	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769556	SCV000900952	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2018-09-04	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001093207	SCV001250069	likely benign	not provided	2022-12-01	criteria provided, single submitter	clinical testing	TGFB2: BS2
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000415640	SCV001366540	likely benign	Loeys-Dietz syndrome 4	2019-05-06	criteria provided, single submitter	clinical testing	This variant was classified as: Likely benign. The following ACMG criteria were applied in classifying this variant: PP4,BP4,BP6.
Baylor Genetics	RCV000415640	SCV001525606	uncertain significance	Loeys-Dietz syndrome 4	2018-03-11	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000196866	SCV002074422	likely benign	not specified	2023-07-10	criteria provided, single submitter	clinical testing	Variant summary: TGFB2 c.356C>T (p.Pro119Leu) 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 0.00039 in 238938 control chromosomes (gnomAD). The observed variant frequency is approximately 311 fold of the estimated maximal expected allele frequency for a pathogenic variant in TGFB2 causing Aortopathy phenotype (1.3e-06), strongly suggesting that the variant is benign. The following publication has been ascertained in the context of this evaluation (PMID: 22772371). Eleven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classifed the variant as VUS (n=4) and benign/likely benign (n=8). Based on the evidence outlined above, the variant was classified as likely benign.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002277545	SCV002566117	likely benign	Ehlers-Danlos syndrome	2019-06-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003947626	SCV004761871	likely benign	TGFB2-related condition	2024-02-15	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).
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000415640	SCV000493806	uncertain significance	Loeys-Dietz syndrome 4	2015-10-23	no assertion criteria provided	clinical testing
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000583868	SCV000692266	uncertain significance	Aortic aneurysm	2017-02-16	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001093207	SCV001927821	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001093207	SCV001957638	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001093207	SCV001970234	likely benign	not provided		no assertion criteria provided	clinical testing