Submissions for variant NM_004612.4(TGFBR1):c.52GCG[12] (p.Ala24_Ala26dup)

dbSNP: rs11466445

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000465262	SCV000548343	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-09-22	criteria provided, single submitter	clinical testing	This variant, c.70_78dup, results in the insertion of 3 amino acid(s) of the TGFBR1 protein (p.Ala24_Ala26dup), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with TGFBR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 408570). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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.
GeneDx	RCV001704558	SCV000566958	likely benign	not provided	2018-08-23	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001704558	SCV002048624	uncertain significance	not provided	2020-11-10	criteria provided, single submitter	clinical testing	The TGFBR1 c.70_78dup; p.Ala24_Ala26dup variant (rs11466445), to our knowledge, has not been reported in the medical literature; however, this variant is listed in the ClinVar database (Variation ID: 408570). This variant is found in the general population with an overall allele frequency of 0.008% (2/23,942 alleles) in the Genome Aggregation Database. This variant is three amino acid, in-frame expansion of the polyalanine track in exon 1 of TGFBR1. In-frame contractions of this track are found at relatively high frequency in the general population and are mostly considered benign (ClinVar; Skoglund 2007). Expansions of this track are less frequent, although a single alanine duplication has been reported in a patient with a Marfan-related disorder (Seo 2018). Based on the available information, the clinical significance of the p.Ala24_Ala26dup variant is uncertain. Seo GH et al. The phenotypic heterogeneity of patients with Marfan-related disorders and their variant spectrums. Medicine (Baltimore). 2018 May;97(20):e10767. Skoglund J et al. Lack of an association between the TGFBR1*6A variant and colorectal cancer risk. Clin Cancer Res. 2007 Jun 15;13(12):3748-52.
Ambry Genetics	RCV000465262	SCV002668124	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2020-08-10	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.