chr9-99138006-C-T

Position:

chr9-99138006-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_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

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 7.86

Variant links:

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]

TGFBR1 links:

TGFBR1 (HGNC:):

TGFBR1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 gene, where missense usually causes diseases (based on misZ statistic), TGFBR1. . Gene score misZ 2.7935 (greater than the threshold 3.09). Trascript score misZ 3.6468 (greater than threshold 3.09). GenCC has associacion of gene with 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/exons	MANE	Protein	UniProt
TGFBR1	NM_004612.4 linkuse as main transcript	c.722C>T	p.Ser241Leu	missense_variant	4/9	ENST00000374994.9	NP_004603.1	P36897-1Q5T7S2B4DXN7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGFBR1	ENST00000374994.9 linkuse as main transcript	c.722C>T	p.Ser241Leu	missense_variant	4/9	1	NM_004612.4	ENSP00000364133.4		P36897-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461746

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727174

show subpopulations

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.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Loeys-Dietz syndrome 1

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	May 15, 2006	- -
Likely pathogenic, criteria provided, single submitter	research	Center of Excellence for Medical Genomics, Chulalongkorn University	Oct 05, 2022	- -

Marfan syndrome;C4551955:Loeys-Dietz syndrome 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Aug 28, 2019

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

Pathogenic, criteria provided, single submitter

clinical testing

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

Oct 24, 2022

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 15, 2023

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TGFBR1 function (PMID: 22414221). 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. ClinVar contains an entry for this variant (Variation ID: 12524). 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. This variant is not present in population databases (gnomAD no frequency). 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). -

Loeys-Dietz syndrome

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

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

Apr 03, 2015

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 30, 2023

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 21, 2015

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

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.48

T;.;.;D;.

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

D;D;D;D;D

M_CAP

Uncertain

0.21

MetaRNN

Pathogenic

0.97

D;D;D;D;D

MetaSVM

Uncertain

0.053

MutationAssessor

Uncertain

2.4

M;.;.;.;.

PrimateAI

Pathogenic

0.88

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over