3-30674105-G-T

Position:

• chr3-30674105-G-T

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.1255G>T​(p.Val419Leu) variant causes a missense, splice region 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. 2/3 splice prediction tools predicting alterations to normal splicing. 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. V419E) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TGFBR2 NM_003242.6 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• 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]

TGFBR2 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a domain Protein kinase (size 300) in uniprot entity TGFR2_HUMAN there are 34 pathogenic changes around while only 5 benign (87%) 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 chr3-30674106-T-A is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.89
• PP5: Variant 3-30674105-G-T is Pathogenic according to our data. Variant chr3-30674105-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 213927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGFBR2	NM_003242.6	c.1255G>T	p.Val419Leu	missense_variant, splice_region_variant	5/7	ENST00000295754.10	NP_003233.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGFBR2	ENST00000295754.10	c.1255G>T	p.Val419Leu	missense_variant, splice_region_variant	5/7	1	NM_003242.6	ENSP00000295754.5
TGFBR2	ENST00000359013.4	c.1330G>T	p.Val444Leu	missense_variant, splice_region_variant	6/8	1		ENSP00000351905.4
TGFBR2	ENST00000672866.1	n.2851G>T		splice_region_variant, non_coding_transcript_exon_variant	5/7
TGFBR2	ENST00000673203.1	n.133G>T		non_coding_transcript_exon_variant	1/3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 05, 2022

The p.V419L variant (also known as c.1255G>T) is located in coding exon 5 of the TGFBR2 gene. The valine at codon 419 is replaced by leucine, an amino acid with highly similar properties. This change occurs in the first base pair of coding exon 5. This variant has been previously reported in an individual with Loeys-Dietz syndrome (LDS) who inherited this allele from his unaffected mother (Cousin MA et al. Cold Spring Harb Mol Case Stud. 2017;3:a001727). In the same study, in vitro assays indicated p.V419L causes deficient TGFBR2 protein function. A different variant causing the same amino acid substitution (c.1255G>C, p.V419L) cosegregates with disease in one family tested in our laboratory (Ambry internal data). A third variant in the same codon, p.V419E, has been reported in a LDS cohort, though clinical details were limited (Jani P et al. J Med Genet, 2020 Oct;57:699-707). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). 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. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 17, 2019

The V419L likely pathogenic variant in the TGFBR2 gene has been published in individual with features suggestive of a heritable connective tissue disorder, including thoracic aortic aneurysm, iliac artery aneurysms, and cervical artery tortuosity (Cousin et al., 2017). Functional analysis demonstrated the V419L variant led to a perturbation in the TFG-beta canonical signaling pathway (Cousin et al., 2017). Though the V419L variant is a conservative amino acid substitution, it occurs at a position within the protein kinase domain that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, missense variants in nearby residues (A414P, A414T, M425V, A426T, P427S, P427L) have been reported in the Human Gene Mutation Database in association TAAD and related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Finally, the V419L variant was not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server), indicating it is not a common benign variant. In summary, V419L in the TGFBR2 gene is interpreted as a likely pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Uncertain	0.097	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	1.5	L;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Uncertain	0.61
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.85
MutPred		0.82		Gain of glycosylation at Y424 (P = 0.0267);.;
MVP		0.99
MPC		1.5
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.90
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.010		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: rs863223847; hg19: chr3-30715597;