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

dbSNP: rs111854391

Total submissions: 8

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	The p.S241L variant (also known as c.722C>T), located in coding exon 4 of the TGFBR1 gene, results from a C to T substitution at nucleotide position 722. The serine at codon 241 is replaced by leucine, an amino acid with dissimilar properties. In one study, p.S241L was detected in two unrelated patients withMarfanoidhabitusanddysmorphiccraniofacialfeatures. One patient had normal intelligence and the other had learning difficulties;craniosynostosiswas present in one patient, but both had pronouncedcraniofacialfeatures. Both patients had aortic dilatation and scoliosis. The p.S241L alteration,located in theserine-threoninekinasedomain, was not detected in the parents of either patient (de novo), the sister of one patient, or 100 control individuals(AdèsLC et al.Am J Med Genet A. 2006;140(10):1047-1058). In another study, p.S241Lwas reported in a patient born in 1971 who fulfilled the diagnostic criteria forMarfansyndrome and also had features supporting the diagnosis ofLoeys-Dietzsyndrome; family history was negative (MátyásG et al.HumMutat. 2006;27(8):760-769). It was also reported in multiple individuals affected by Loeys-Dietz syndrom(LoeysBLet al.NEnglJ Med. 2006;355(8):788-798;StheneurC et al, Hum.Mutat. 2008 Nov; 29(11):E284-95;NishidaK et al,PediatrInt 2014 Dec; 56(6):e82-5). With patient derived fibroblasts, it was shown that this variant cause decreased elastin and fibulin 1 mRNA expression, and also impaired the deposition of elastin, fibrillin 1 and fibulin 1 into elastic fibers (Barnett CP et al, Eur. J. Hum. Genet. 2011 Jun; 19(6):624-33). An in vitro study suggested the alteration negativelyaffected both the basal and TGF-beta induced Smad signaling (CardosoS et al, J.Recept. SignalTransduct. Res. 2012Jun; 32(3):150-5).This variant was previously reported in the SNPDatabase as rs111854391, butnot found in population-based cohorts in the following databases:NHLBIExomeSequencing Project (ESP) and 1000 Genomes Project.This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive.Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneDx	RCV000442105	SCV000521077	pathogenic	not provided	2023-10-30	criteria provided, single submitter	clinical testing	Published functional studies suggest that the S241L variant adversely affects the activation of TGFR1 by TGFR2 (PMID: 22414221); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25521989, 23884466, 16791849, 18781618, 25944730, 21267002, 16928994, 27879313, 26133393, 18852674, 28209770, 28743916, 28152038, 31915033, 33822359, 32152251, 33436942, 30787465, 34916229, 34456093, 35586607, 35753512, 16596670, 22414221)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000244262	SCV000548341	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2023-05-15	criteria provided, single submitter	clinical testing	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. Experimental studies have shown that this missense change affects TGFBR1 function (PMID: 22414221). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 12524). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 241 of the TGFBR1 protein (p.Ser241Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Loeys-Dietz syndrome and Furlong syndrome and aortic dissection and clinical features of Loeys-Dietz syndrome (PMID: 16596670, 16791849, 18781618, 23884466, 25521989, 25944730, 28209770). In at least one individual the variant was observed to be de novo.
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.
Center of Excellence for Medical Genomics, Chulalongkorn University	RCV000013350	SCV002583254	likely pathogenic	Loeys-Dietz syndrome 1	2022-10-05	criteria provided, single submitter	research
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224094	SCV003920553	pathogenic	Loeys-Dietz syndrome 1; Multiple self-healing squamous epithelioma	2022-10-24	criteria provided, single submitter	clinical testing	This variant has been reported in the literature in at least 10 individuals with clinical features suggestive of, or consistent with, Loeys-Dietz syndrome (Selected publications: Wooderchak-Donahue 2015 PIMD: 25944730; Jani 2020 PMID: 32152251; Yang 2020 PMID: 31915033; Nayak 2021 PMID: 33436942), and was found to segregate with disease in a mildly affected parent (Woolnough 2017 PMID: 28209770). In at least two individuals, the variant was determined to be de novo (Adès 2006 PMID: 16596670). This variant is not present in large control databases but is present in ClinVar, with multiple laboratories classifying it as pathogenic or likely pathogenic (Variation ID: 12524). Functional studies in vitro and in patient-derived fibroblasts demonstrate that this variant impacts protein function (Barnett 2011 PMID: 21267002; Cardoso 2012 PMID: 22414221). Evolutionary conservation and computational prediction tools support a deleterious effect of this variant. In summary, this variant is classified as pathogenic.
OMIM	RCV000013350	SCV000033597	pathogenic	Loeys-Dietz syndrome 1	2006-05-15	no assertion criteria provided	literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000030540	SCV000053211	pathogenic	Loeys-Dietz syndrome	2015-04-03	no assertion criteria provided	clinical testing