Submissions for variant NM_003242.6(TGFBR2):c.938G>A (p.Arg313Gln)

gnomAD frequency: 0.00004  dbSNP: rs200361387

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000688154	SCV000815756	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 313 of the TGFBR2 protein (p.Arg313Gln). This variant is present in population databases (rs200361387, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with TGFBR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 567942). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt TGFBR2 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.
Fulgent Genetics, Fulgent Genetics	RCV000765722	SCV000897089	uncertain significance	Loeys-Dietz syndrome 2; Malignant tumor of esophagus; Colorectal cancer, hereditary nonpolyposis, type 6	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000688154	SCV000905699	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2024-03-06	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 313 of the TGFBR2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). 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 15/282456 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.
GeneDx	RCV000998013	SCV001769632	uncertain significance	not provided	2025-02-03	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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003994082	SCV004813971	likely benign	not specified	2024-02-27	criteria provided, single submitter	clinical testing	Variant summary: TGFBR2 c.938G>A (p.Arg313Gln) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 251058 control chromosomes. The observed variant frequency is approximately 40 fold of the estimated maximal expected allele frequency for a pathogenic variant in TGFBR2 causing Aortopathy phenotype (1.3e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.938G>A in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 567942). Based on the evidence outlined above, the variant was classified as likely benign.
All of Us Research Program, National Institutes of Health	RCV004004276	SCV004839207	uncertain significance	Loeys-Dietz syndrome 2	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 313 of the TGFBR2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 15/282456 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.
Ambry Genetics	RCV000688154	SCV005514900	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2024-11-08	criteria provided, single submitter	clinical testing	The c.938G>A (p.R313Q) alteration is located in exon 4 (coding exon 4) of the TGFBR2 gene. This alteration results from a G to A substitution at nucleotide position 938, causing the arginine (R) at amino acid position 313 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.