ClinVar Miner

Submissions for variant NM_004612.4(TGFBR1):c.207C>T (p.Ser69=) (rs145033378)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000621633 SCV000739740 likely benign Cardiovascular phenotype 2017-12-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: RNA Studies
Color RCV000231583 SCV000913783 likely benign Thoracic aortic aneurysm and aortic dissection 2018-05-29 criteria provided, single submitter clinical testing
GeneDx RCV000199569 SCV000250869 uncertain significance not provided 2018-10-02 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the TGFBR1 gene. The S69S (c.207 C>T) synonymous amino acid substitution was identified in one individual from a cohort of Marfan/Loeys Dietz syndrome patients and reported as a potentially disease-causing variant (Kathiravel et al., 2013). The c.207 C>T variant is observed in 19/34346 (0.05%) alleles from individuals of Latino ancestry and in 27/126246 (0.02%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). Although this nucleotide position is not conserved and thymine (T) is tolerated in several species, in silico splice prediction programs predict this variant creates a cryptic splice donor site that is upstream of the natural splice donor site, which may lead to aberrant gene splicing. However, in the absence of functional mRNA studies, the physiological consequence of this variant cannot be precisely determined. Furthermore, haploinsufficiency in TGFBR1 due to loss-of-function variants have only been reported in in association with multiple self-healing squamous epithelioma (MSSE) (Stenson et al., 2014), and loss of function is not an established disease mechanism for Loeys-Dietz syndrome (LDS). Finally, although this variant has also been identified in multiple individuals referred for Marfan/TAAD testing at GeneDx, segregation data is thus far uninformative or absent.
Invitae RCV000231583 SCV000288618 likely benign Thoracic aortic aneurysm and aortic dissection 2017-04-24 criteria provided, single submitter clinical testing

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