3-30672250-G-C

Position:

• chr3-30672250-G-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_003242.6(TGFBR2):​c.1067G>C​(p.Arg356Pro) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R356G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TGFBR2 NM_003242.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 10.0

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 Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 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 chr3-30672249-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 213920.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=2}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.914
• PP5: Variant 3-30672250-G-C is Pathogenic according to our data. Variant chr3-30672250-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 177704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGFBR2	NM_003242.6	c.1067G>C	p.Arg356Pro	missense_variant	4/7	ENST00000295754.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGFBR2	ENST00000295754.10	c.1067G>C	p.Arg356Pro	missense_variant	4/7	1	NM_003242.6	P1
TGFBR2	ENST00000359013.4	c.1142G>C	p.Arg381Pro	missense_variant	5/8	1
TGFBR2	ENST00000672866.1	n.2663G>C		non_coding_transcript_exon_variant	4/7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1450824 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 720178

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 16, 2020

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). This variant has been observed in individual(s) with TGFBR2-related conditions (PMID: 16283890, 16835936, 22095581, 24220024, 27611364). In at least one individual the variant was observed to be de novo. This variant is also known as c.1142G>C (p.Arg381Pro) in the literature. ClinVar contains an entry for this variant (Variation ID: 177704). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with proline at codon 356 of the TGFBR2 protein (p.Arg356Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. -

Loeys-Dietz syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 29, 2014

The Arg356Pro variant in TGFBR2 has been reported in 5 individuals with clinical features of Loeys-Dietz syndrome and was found to occur de novo in 3 of these i ndividuals (Ki 2005, Sakai 2006, Uike 2013, Amor 2012, LMM unpublished data). Th is variant was absent from large population studies. Computational prediction to ols and conservation analysis suggest that the Arg356Pro variant may impact the protein, though this information is not predictive enough to determine pathogeni city. In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM) based upon segregation studies and absence from controls. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Mar 10, 2023

- -

Loeys-Dietz syndrome 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Nov 30, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Uncertain	0.00010	D
MutationAssessor	Uncertain	2.6	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-5.0	D;D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.051	T;T
Polyphen		0.99	D;.
Vest4		0.71
MutPred		0.83		Loss of MoRF binding (P = 0.007);.;
MVP		0.89
MPC		1.7
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.97
gMVP		0.94

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: rs727504292; hg19: chr3-30713742; COSMIC: COSV55444676;