9-99138006-C-T

Variant names:

• chr9-99138006-C-T
• rs111854391
• NM_004612.4:c.722C>T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_004612.4(TGFBR1):​c.722C>T​(p.Ser241Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,746 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TGFBR1 NM_004612.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 7.86

Genes affected

TGFBR1 (HGNC:11772): (transforming growth factor beta receptor 1) The protein encoded by this gene forms a heteromeric complex with type II TGF-beta receptors when bound to TGF-beta, transducing the TGF-beta signal from the cell surface to the cytoplasm. The encoded protein is a serine/threonine protein kinase. Mutations in this gene have been associated with Loeys-Dietz aortic aneurysm syndrome (LDAS). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2008]

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM1: In a helix (size 10) in uniprot entity TGFR1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_004612.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the TGFBR1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 48 curated pathogenic missense variants (we use a threshold of 10). The gene has 16 curated benign missense variants. Gene score misZ: 2.7935 (below the threshold of 3.09). Trascript score misZ: 3.6468 (above the threshold of 3.09). GenCC associations: The gene is linked to familial thoracic aortic aneurysm and aortic dissection, Loeys-Dietz syndrome, multiple self-healing squamous epithelioma, Loeys-Dietz syndrome 1.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968
• PP5: Variant 9-99138006-C-T is Pathogenic according to our data. Variant chr9-99138006-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12524.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-99138006-C-T is described in Lovd as [Likely_pathogenic]. Variant chr9-99138006-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBR1	NM_004612.4	c.722C>T	p.Ser241Leu	missense_variant	Exon 4 of 9	ENST00000374994.9	NP_004603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFBR1	ENST00000374994.9	c.722C>T	p.Ser241Leu	missense_variant	Exon 4 of 9	1	NM_004612.4	ENSP00000364133.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461746 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727174

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Loeys-Dietz syndrome 1 Pathogenic:2

May 15, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 05, 2022

Center of Excellence for Medical Genomics, Chulalongkorn University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Marfan syndrome;C4551955:Loeys-Dietz syndrome 1 Pathogenic:1

Aug 28, 2019

Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Multiple self-healing squamous epithelioma;C4551955:Loeys-Dietz syndrome 1 Pathogenic:1

Oct 24, 2022

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

May 15, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Loeys-Dietz syndrome Pathogenic:1

Apr 03, 2015

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Pathogenic:1

Oct 30, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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) -

Cardiovascular phenotype Pathogenic:1

Sep 21, 2015

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.48	T;.;.;D;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Uncertain	0.053	D
MutationAssessor	Uncertain	2.4	M;.;.;.;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.8	D;D;D;D;D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;D;.;.;.
Vest4		0.94
MutPred		0.90		Loss of disorder (P = 0.0051);.;.;.;.;
MVP		0.96
MPC		3.1
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.85
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs111854391; hg19: chr9-101900288; COSMIC: COSV66624834;