ClinVar Miner

Submissions for variant NM_004612.4(TGFBR1):c.722C>T (p.Ser241Leu) (rs111854391)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000617152 SCV000318311 likely pathogenic Cardiovascular phenotype 2015-09-21 criteria provided, single submitter clinical testing In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Rarity in general population databases (dbsnp, esp, 1000 genomes);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Deficient protein function in appropriate functional assay(s)
GeneDx RCV000442105 SCV000521077 pathogenic not provided 2018-04-04 criteria provided, single submitter clinical testing The S241L pathogenic variant in the TGFBR1 gene has been reported in multiple individuals with a diagnosis of Loeys-Dietz syndrome and was identified as a de novo variant in at least four cases (Mátyás et al., 2006; Adès et al., 2006; Stheneur et al., 2008; Nishida et al., 2014; Wooderchak-Donahue et al., 2015). In addition, the S241L pathogenic variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The S241L variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Furthermore, this substitution is located within the protein kinase domain at a position that is conserved across species.
Invitae RCV000244262 SCV000548341 pathogenic Familial thoracic aortic aneurysm and aortic dissection 2018-11-07 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 241 of the TGFBR1 protein (p.Ser241Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is not present in population databases (rs111854391, ExAC no frequency). In addition, this variant has been observed to be de novo in individuals affected with Furlong syndrome (PMID: 16596670), in an individual with Loeys-Dietz syndrome (PMID: 18781618), and in an individual with aortic dissection (PMID: 28209770).This variant has also been observed in individuals with clinical features of Loeys-Dietz syndrome (PMID: 25521989, 25944730, 23884466, 16791849, 28209770).ClinVar contains an entry for this variant (Variation ID: 12524). Experimental studies have shown that this missense change has an inhibitory effect on TGFBR1 activity (PMID: 22414221). For these reasons, this variant has been classified as Pathogenic.
Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations RCV000845292 SCV000986693 pathogenic Loeys-Dietz syndrome 1; Marfan syndrome 2019-08-28 criteria provided, single submitter clinical testing The p.Ser241Leu variant was found in one individual with Marfanoid phenotype at our clinical center. This variant is a known mutation associated with a Loeys-Dietz syndrome (PMID: 16596670, 16791849, 16928994, 27879313) and was also found in patients with colorectal cancer (PMID: 28743916) with a functional consequences of the variant. The S241L variant has a very low frequency (rs111854391). ClinVar has an entry for this variant (Variation ID: 12524). Based on this evidences the p.Ser241Leu is classified as Pathogenic.
OMIM RCV000013350 SCV000033597 pathogenic Loeys-Dietz syndrome 1 2006-05-15 no assertion criteria provided literature only
Integrated Genetics/Laboratory Corporation of America RCV000030540 SCV000053211 pathogenic Loeys-Dietz syndrome 2015-04-03 no assertion criteria provided clinical testing

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