Submissions for variant NM_004612.4(TGFBR1):c.929C>T (p.Ala310Val)

gnomAD frequency: 0.00005  dbSNP: rs202010361

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000770354	SCV000739737	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2021-11-01	criteria provided, single submitter	clinical testing	The p.A310V variant (also known as c.929C>T), located in coding exon 5 of the TGFBR1 gene, results from a C to T substitution at nucleotide position 929. The alanine at codon 310 is replaced by valine, an amino acid with similar properties. This alteration has been reported in a Loeys-Dietz syndrome cohort; however, clinical details were limited (Yang H et al. Orphanet J Rare Dis, 2020 01;15:6). 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 alteration remains unclear.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770354	SCV000901794	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2016-07-25	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000770354	SCV001344049	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-05-01	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 310 of the TGFBR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with thoracic aortic aneurysm and dissection (PMID: 31915033). This variant has been identified in 6/282484 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	RCV000770354	SCV001391755	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-06-20	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 310 of the TGFBR1 protein (p.Ala310Val). This variant is present in population databases (rs202010361, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of Loeys-Dietz syndrome (PMID: 31915033). ClinVar contains an entry for this variant (Variation ID: 520216). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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	RCV002491331	SCV002777347	uncertain significance	Loeys-Dietz syndrome 1; Multiple self-healing squamous epithelioma	2021-09-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003411466	SCV004116068	uncertain significance	TGFBR1-related disorder	2022-10-14	criteria provided, single submitter	clinical testing	The TGFBR1 c.929C>T variant is predicted to result in the amino acid substitution p.Ala310Val. This variant was reported with uncertain significance in a study of Chinese individuals with Loeys-Dietz syndrome (Yang et al. 2020. PubMed ID: 31915033). This variant is reported in 0.024% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-101904941-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health	RCV004002733	SCV004840406	uncertain significance	Loeys-Dietz syndrome	2023-06-08	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 310 of the TGFBR1 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >=0.7, 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 been identified in 6/282484 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.