Submissions for variant NM_004612.4(TGFBR1):c.199C>T (p.His67Tyr)

gnomAD frequency: 0.00002  dbSNP: rs766157497

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000756777	SCV000884687	uncertain significance	not provided	2017-10-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780773	SCV000918306	uncertain significance	not specified	2017-11-20	criteria provided, single submitter	clinical testing	Variant summary: The TGFBR1 c.199C>T (p.His67Tyr) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 2/214840 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.000131 (2/15300). This frequency is about 75 times the estimated maximal expected allele frequency of a pathogenic TGFBR1 variant (0.0000018), suggesting this is possibly a benign polymorphism found primarily in the populations of African origin, although the allele number is small. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as VUS-possibly benign.
Color Diagnostics, LLC DBA Color Health	RCV001179697	SCV001344407	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-11-22	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with tyrosine at codon 67 of the TGFBR1 protein. Computational prediction suggests that this variant may have a neutral 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 TGFBR1-related disorders in the literature. This variant has been identified in 2/250852 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001179697	SCV002248604	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2023-12-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001179697	SCV002724184	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2021-08-07	criteria provided, single submitter	clinical testing	The p.H67Y variant (also known as c.199C>T), located in coding exon 2 of the TGFBR1 gene, results from a C to T substitution at nucleotide position 199. The histidine at codon 67 is replaced by tyrosine, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002500976	SCV002816104	uncertain significance	Loeys-Dietz syndrome 1; Multiple self-healing squamous epithelioma	2021-09-16	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003999888	SCV004840365	uncertain significance	Loeys-Dietz syndrome	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with tyrosine at codon 67 of the TGFBR1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified 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.