9-99137963-G-A

Variant names:

• chr9-99137963-G-A
• rs1060502042
• NM_004612.4:c.679G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3 PP5

The NM_004612.4(TGFBR1):​c.679G>A​(p.Glu227Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TGFBR1 NM_004612.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 9.94

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a strand (size 7) 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, 0.8
• PP5: Variant 9-99137963-G-A is Pathogenic according to our data. Variant chr9-99137963-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 408566.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBR1	NM_004612.4	c.679G>A	p.Glu227Lys	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.679G>A	p.Glu227Lys	missense_variant	Exon 4 of 9	1	NM_004612.4	ENSP00000364133.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1 Uncertain:1

Sep 26, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 227 of the TGFBR1 protein (p.Glu227Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with aortic dissection (Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 408566). 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. For these reasons, this variant has been classified as Pathogenic. -

Nov 09, 2018

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E227K variant (also known as c.679G>A), located in coding exon 4 of the TGFBR1 gene, results from a G to A substitution at nucleotide position 679. The glutamic acid at codon 227 is replaced by lysine, an amino acid with similar properties, and is located in the protein kinase domain. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided Pathogenic:1

Jul 27, 2016

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

p.Glu227Lys (c.679G>A) in the TGFBR1 gene (NM_004612.2) The lab classifies this variant as a variant of unknown significance. Given the patient's phenotype is consistent with Loeys-Dietz syndrome and there is lack of variation at this position in the general population and through evolution we consider this variant likely disease causing. This variant was not inherited from the patient's father and was likely inherited by the patient's mother who passed from an aortic dissection at 4.5 cm (at the AoSV) which indicates that she likely had Loeys-Dietz syndrome given her relatively small aortic diameter at the time of dissection. The variant is novel in this family. One of the patient's sisters who has hypermobility and a long uvula also tested positive for this variant. Cardiac evaluation is pending. In silico analysis with PolyPhen-2 predicts the variant to be pathogenic (HumVar: 0.998) and mutation taster agrees (0.999). The glutamic acid at codon 227 is conserved across species, as are neighboring amino acids. This variant is located in the catalytic kinase domain of the extracellular protein component and likely inhibits binding through the catalytic kinase domain. Other variants in this domain have been shown to be pathogenic. There is no variation at codon 227 listed in the Genome Aggregation database (http://gnomad.broadinstitute.org/), which currently includes variant calls on ~140,000 individuals of European, African, Latino and Asian descent (as of Jan 31, 2017) indicating that variation at this position is extremely rare. There is no variation listed in the gnomad database between codons 223 and 233 indicating that this area of the protein is not tolerant of missense variation and likely disrupts protein function. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.42	T;.;.;T;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D;D
M_CAP	Benign	0.039	D
MetaRNN	Pathogenic	0.80	D;D;D;D;D
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	1.7	L;.;.;.;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.4	D;D;D;D;D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0050	D;D;D;D;D
Sift4G	Uncertain	0.0070	D;D;D;D;D
Polyphen		1.0	D;B;.;.;.
Vest4		0.71
MutPred		0.64		Loss of ubiquitination at K232 (P = 0.0477);.;.;.;.;
MVP		0.94
MPC		3.5
ClinPred		0.97	D
GERP RS		5.6
Varity_R		0.93
gMVP		0.90

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: rs1060502042; hg19: chr9-101900245; COSMIC: COSV66625785;