Submissions for variant NM_004612.4(TGFBR1):c.1420T>C (p.Cys474Arg)

dbSNP: rs759805984

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000198521	SCV000250897	likely pathogenic	not provided	2013-02-21	criteria provided, single submitter	clinical testing	p.Cys474Arg (TGT>CGT): c.1420 T>C in exon 9 of the TGFBR1 gene (NM_004612.2)The Cys474Arg variant in the TGFBR1 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Cys474Arg results in a non-conservative amino acid substitution of a neutral Cysteine with a positively charged Arginine, which is likely to disrupt disulfide bonds in the DNA. This substitution occurs at a position that is well conserved across species, and consequently, in silico analysis predicts Cys474Arg is probably damaging to the protein structure/function. Mutations in nearby residues (Asn478Ser, Leu486Ser) have been reported in association with TAAD, further supporting the functional importance of this region of the protein. In addition, the Cys474Arg variant was not observed in approximately 6000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, while Cys474Arg in the TGFBR1 gene is a good candidate for a disease-causing mutation, with the clinical and molecular information available at this time we cannot unequivocally determine the clinical significance of this variant. This variant was found in TAAD
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000198521	SCV004026279	likely pathogenic	not provided	2023-02-22	criteria provided, single submitter	clinical testing	PM1, PP3, PP2, PS4, PM2_SUP