Submissions for variant NM_003238.6(TGFB2):c.1141G>A (p.Val381Met)

gnomAD frequency: 0.00001  dbSNP: rs376159002

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002315241	SCV000739709	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2024-12-02	criteria provided, single submitter	clinical testing	The c.1141G>A (p.V381M) alteration is located in exon 7 (coding exon 7) of the TGFB2 gene. This alteration results from a G to A substitution at nucleotide position 1141, causing the valine (V) at amino acid position 381 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Ambry Genetics	RCV000624548	SCV000742778	uncertain significance	Inborn genetic diseases	2017-09-05	criteria provided, single submitter	clinical testing
GeneDx	RCV002274072	SCV002559543	uncertain significance	not provided	2023-03-23	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function
Fulgent Genetics, Fulgent Genetics	RCV002483736	SCV002781944	uncertain significance	Loeys-Dietz syndrome 4	2021-07-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002483736	SCV004538915	uncertain significance	Loeys-Dietz syndrome 4	2024-09-11	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 381 of the TGFB2 protein (p.Val381Met). This variant is present in population databases (rs376159002, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with TGFB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 520200). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt TGFB2 protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004702201	SCV005204602	likely benign	not specified	2024-06-19	criteria provided, single submitter	clinical testing	Variant summary: TGFB2 c.1141G>A (p.Val381Met) results in a conservative amino acid change located in the transforming growth factor-beta, C-terminal (IPR001839) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.2e-05 in 1613594 control chromosomes (gnomAD v4.1.0). The observed variant frequency is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in TGFB2 causing Thoracic Aortic Aneurysms And Dissections phenotype (2.5e-05). To our knowledge, no occurrence of c.1141G>A in individuals affected with Thoracic Aortic Aneurysms And Dissections and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 520200). Based on the evidence outlined above, the variant was classified as likely benign.