ClinVar Miner

Submissions for variant NM_003242.6(TGFBR2):c.367A>T (p.Met123Leu) (rs768385200)

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Total submissions: 9
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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 2017-12-27 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, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Illumina Clinical Services Laboratory,Illumina RCV000323333 SCV000442835 likely benign Loeys-Dietz syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000380176 SCV000442836 likely benign Marfan syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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
Invitae RCV000253449 SCV000658829 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2020-10-28 criteria provided, single submitter clinical testing This sequence change replaces methionine with leucine at codon 123 of the TGFBR2 protein (p.Met123Leu). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and leucine. This variant is present in population databases (rs768385200, ExAC 0.05%). This variant has not been reported in the literature in individuals with TGFBR2-related disease. ClinVar contains an entry for this variant (Variation ID: 213939). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). 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.
Color Health, Inc RCV000253449 SCV001358499 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2020-12-23 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.
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.

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