Submissions for variant NM_004612.4(TGFBR1):c.605C>T (p.Ala202Val)

dbSNP: rs1564161322

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000798557	SCV000938178	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2023-07-21	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TGFBR1 protein function. ClinVar contains an entry for this variant (Variation ID: 635251). This missense change has been observed in individuals with clinical features of Loeys-Dietz syndrome (PMID: 27146836, 27879313, 31915033; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 202 of the TGFBR1 protein (p.Ala202Val).
CeGaT Center for Human Genetics Tuebingen	RCV000786409	SCV001155688	uncertain significance	not provided	2019-05-01	criteria provided, single submitter	clinical testing
Department of Vascular Biology, Beijing Anzhen Hospital	RCV001374785	SCV001439502	uncertain significance	Isolated thoracic aortic aneurysm	2018-09-01	criteria provided, single submitter	research
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786409	SCV000925227	uncertain significance	not provided	2016-11-08	no assertion criteria provided	provider interpretation	The patient had genetic testing by the Collagen Diagnostics Laboratory. It looked for variants in 15 genes associated with aneurysms and dissections: ACTA2, COL3A1, FBN1, FBN2, MAT2A, MYH11, MYLK, MYH11, PRKG1, SKI, SLC2A10, SMAD3, TGFB3, TGFBR1, TGFBR2. Results reported on October 24, 2016 show that a variant was found: p.Ala202Val in the TGFBR1 gene. See report below. p.Ala202Val (c.605C>T) in the TGFBR1 gene The lab classifies this variant as a variant of unknown significance. Given insufficient case data, and lack of segregation data we consider this variant a variant of unknown significance, but is highly suspicious. At this time we recommend further family studies to determine if this variant segregates with disease in the family. Currently we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least four unrelated cases of Loeys-Dietz syndrome as detailed below (not including this patient's family). There is no segregation data. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging (HumVar = 1.00). The alanine at codon 202 is conserved across all 99 species, as are neighboring amino acids. This substituted amino acid is located between the glycine-serine-rich domain (GS domain that contains sites of activating phosphorylation) and the kinase domain (the catalytic domain ) of the type I TGFb receptor. At this time function of this junction region is not well characterized. Within this region, substitution at position 200 (p.Thr200Ile) was previously reported in a young child with Loeys-Dietz syndrome (Loeys et al, 2005). CDL has previously seen substitutions at positions 199 (p.Arg199Lys), 204 (p.Thr204Ile) and 205 (p.Ile205Thr) in individuals tested due to aortic aneurysms, however we have not been able to establish whether those variants are pathogenic. None of these nearby variants have been previously identified in the exac or gnomad browsers (indicating that they're sufficiently rare). There are three individuals with variation at position 202 listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. The average coverage at that site in gnomAD is unavailable as of 10/31/2016.
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	RCV001528128	SCV001739336	likely pathogenic	Loeys-Dietz syndrome 1	2021-04-15	no assertion criteria provided	clinical testing