3-30691475-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3_Moderate PP5

The NM_003242.6(TGFBR2):c.1580C>T(p.Ala527Val) 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A527T) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TGFBR2 NM_003242.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 7.91

Genes affected

TGFBR2 (HGNC:11773): (transforming growth factor beta receptor 2) The protein encoded by this gene is a transmembrane protein that has a protein kinase domain, forms a heterodimeric complex with TGF-beta receptor type-1, and binds TGF-beta. This receptor/ligand complex phosphorylates proteins, which then enter the nucleus and regulate the transcription of genes related to cell proliferation, cell cycle arrest, wound healing, immunosuppression, and tumorigenesis. Mutations in this gene have been associated with Marfan Syndrome, Loeys-Deitz Aortic Aneurysm Syndrome, and the development of various types of tumors. Alternatively spliced transcript variants encoding different isoforms have been characterized. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_003242.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-30691474-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1066978.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.895
• PP5: Variant 3-30691475-C-T is Pathogenic according to our data. Variant chr3-30691475-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 165398.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGFBR2	NM_003242.6	c.1580C>T	p.Ala527Val	missense_variant	7/7	ENST00000295754.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGFBR2	ENST00000295754.10	c.1580C>T	p.Ala527Val	missense_variant	7/7	1	NM_003242.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 26, 2018	The p.A527V variant (also known as c.1580C>T), located in coding exon 7 of the TGFBR2 gene, results from a C to T substitution at nucleotide position 1580. The alanine at codon 527 is replaced by valine, an amino acid with similar properties, and is located in the cbEGF-like #03 domain. This alteration has been reported in an individual with Loeys-Dietz syndrome (LDS) (Loeys BL et al. N. Engl. J. Med., 2006 Aug;355:788-98). An alternate substitution at this position, p.A527T (c.1579G>A), has also been associated with LDS (Poninska JK et al. J Transl Med, 2016 May;14:115). The current alteration and the close match, p.A527T, have both been reported in a LDS cohort, but limited clinical details were provided (Frischmeyer-Guerrerio PA et al. Sci Transl Med, 2013 Jul;5:195ra94). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 24, 2023	This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 527 of the TGFBR2 protein (p.Ala527Val). This missense change has been observed in individuals with TGFBR2-related disease (PMID: 16928994, 18852674; Invitae). ClinVar contains an entry for this variant (Variation ID: 165398). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt TGFBR2 function. This variant disrupts the p.Ala527 amino acid residue in TGFBR2. Other variant(s) that disrupt this residue have been observed in individuals with TGFBR2-related conditions (PMID: 27146836, 27508510), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Loeys-Dietz syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Sep 07, 2016

Variant summary: The TGFBR2 c.1580C>T (p.Ala527Val) variant involves the alteration of a highly conserved nucleotide and is located in the protein kinase domain of the protein (InterPro, UniProt). The alanine residue at this codon is highly conserved across species, and 4/4 in silico tools predict a damaging outcome for this variant. This variant was absent in 121254 control chromosomes from the broad and large populations of ExAC. In the literature, this variant was reported as a pathogenic variant found in three patients with Loeys-Dietz syndrome (Loeys_2006, Frischmeyer-Guerrerio_2013). Another missense change at the same residue, p.Ala527Thr, has also been reported in patients with Loeys-Dietz syndrome (Frischmeyer-Guerrerio_2013, Poninska_ J Transl Med_2016). In addition, several other potentially/likely pathogenic variants, such as p.Asp524Asn, p.Glu526Gln, p.Arg528Cys, p.Arg528His, and p.Ala531Thr have also been reported in this region, suggesting the region is mutational hot-spot. Furthermore, one reputable database has classified it as disease-causing. Taken together, this variant is currently classified as Likely Pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 15, 2022

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: 23884466, 27508510, 27146836, 18852674, 16928994, 17061023) -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 15, 2011

Variant classified as Uncertain Significance - Favor Pathogenic. The Ala527Val v ariant has been previously reported in 1 individual with clinical features of Lo eys-Dietz syndrome and was absent from 200 control chromosomes (Loeys 2006). Ala nine (Ala) at position 527 is highly conserved across evolutionarily distant spe cies, increasing the likelihood that the change is pathogenic. However, computer predictions are mixed (AlignGVGD = benign, Polyphen2 & SIFT = pathogenic), thou gh these tools have not been validated sufficiently to assume pathogenicity. Alt hough these data suggests that the Ala527Val variant may be disease causing, add itional information is required to fully assess this variant. Therefore, the cli nical significance of this variant cannot be determined at this time. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Uncertain	-0.079	T
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.6	D;D
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.73
MutPred		0.84		Gain of glycosylation at T530 (P = 0.0201);.;
MVP		0.91
MPC		1.5
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.74
gMVP		0.75

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: rs727503476; hg19: chr3-30732967;