Submissions for variant NM_003242.6(TGFBR2):c.367A>T (p.Met123Leu)

gnomAD frequency: 0.00010  dbSNP: rs768385200

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766907	SCV000250960	uncertain significance	not provided	2018-11-01	criteria provided, single submitter	clinical testing	The M123L variant of uncertain significance in the TGFBR2 gene has not been published as a pathogenic or benign variant to our knowledge. This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project or with any significant frequency in the Exome Aggregation Consortium, indicating it is not a common benign variant in these populations. The M123L variant has been identified in several other individuals referred for Marfan/TAAD genetic testing at GeneDx; however, the majority of individuals harbored a second cardiogenetic variant. This substitution occurs at a position that is conserved across species, and the majority of in silico tools predict this variant is probably damaging to the protein structure/function. Nevertheless, the M123L variant is a conservative amino acid substitution, which may not impact secondary protein structure as these residues share similar properties. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Ambry Genetics	RCV000253449	SCV000320500	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-03-08	criteria provided, single submitter	clinical testing	The p.M123L variant (also known as c.367A>T), located in coding exon 3 of the TGFBR2 gene, results from an A to T substitution at nucleotide position 367. The methionine at codon 123 is replaced by leucine, an amino acid with some highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Illumina Laboratory Services, Illumina	RCV000323333	SCV000442835	likely benign	Loeys-Dietz syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000380176	SCV000442836	likely benign	Marfan syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000253449	SCV000442837	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2016-06-14	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000198358	SCV000605376	uncertain significance	not specified	2017-01-06	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000253449	SCV000658829	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2024-01-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000253449	SCV001358499	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-11-29	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with leucine at codon 123 of the TGFBR2 protein. Computational prediction tool indicates that this variant may have an uncertain impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with TGFBR2-related disorders in the literature. This variant has been identified in 11/282168 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Revvity Omics, Revvity	RCV000766907	SCV003819486	uncertain significance	not provided	2022-03-11	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003996930	SCV004839160	uncertain significance	Loeys-Dietz syndrome 2	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with leucine at codon 123 of the TGFBR2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 11/282168 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV004020382	SCV005016460	uncertain risk allele	Diabetic retinopathy		criteria provided, single submitter	research	Potent mutations in TGFBR2 gene encodes the transforming growth factor that have been associated with angiogenesis and diabetic retinopathy. More clinical studies are needed for stronger association. However, more evidence is required to confer the association of this particular variant rs768385200 with diabetic retinopathy.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000766907	SCV001553491	uncertain significance	not provided		no assertion criteria provided	clinical testing	The TGFBR2 p.Met123Leu variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs768385200), LOVD 3.0 and ClinVar (classified as uncertain significance by GeneDx, Ambry Genetics, ARUP Laboratories and Invitae, and as likely benign by Illumina). The variant was identified in control databases in 9 of 267632 chromosomes at a frequency of 0.00003363 (Genome Aggregation Database March 6, 2019, v2.1.1, non-cancer). The variant was observed in the following populations: Other in 2 of 6684 chromosomes (freq: 0.000299), East Asian in 3 of 19248 chromosomes (freq: 0.000156), Latino in 3 of 35078 chromosomes (freq: 0.000086) and African in 1 of 23596 chromosomes (freq: 0.000042), but was not observed in the Ashkenazi Jewish, European (Finnish), European (non-Finnish), or South Asian populations. The p.Met123 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.