9-99142665-G-T

Variant names:

• chr9-99142665-G-T
• rs869025535
• NM_004612.4:c.935G>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_004612.4(TGFBR1):​c.935G>T​(p.Gly312Val) 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G312D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TGFBR1 NM_004612.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Loeys-Dietz syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Loeys-Dietz syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia, Genomics England PanelApp, G2P
• multiple self-healing squamous epithelioma

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain in NM_004612.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-99142664-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 213882.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBR1	NM_004612.4	c.935G>T	p.Gly312Val	missense_variant	Exon 5 of 9	ENST00000374994.9	NP_004603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFBR1	ENST00000374994.9	c.935G>T	p.Gly312Val	missense_variant	Exon 5 of 9	1	NM_004612.4	ENSP00000364133.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Mar 18, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TGFBR1 c.935G>T; p.Gly312Val variant is reported in the literature in an individual affected with Loeys-Dietz syndrome (Yang 2020). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The glycine at codon 312 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, another amino acid substitution at this codon (p.Gly312Ser) has been reported in individuals and families with Loeys-Dietz syndrome or a related aortopathy and is considered diseae-causing (Singh 2006, Teixido-Tura 2016, Yang 2020). While current evidence suggests a possible association with disease, given the lack of clinical and functional data, the significance of the p.Gly312Val variant is uncertain at this time. References: Singh KK et al. TGFBR1 and TGFBR2 mutations in patients with features of Marfan syndrome and Loeys-Dietz syndrome. Hum Mutat. 2006 Aug;27(8):770-7. Teixido-Tura G et al. Heterogeneity of aortic disease severity in patients with Loeys-Dietz syndrome. Heart. 2016 Apr;102(8):626-32. Yang H et al. Genetic profiling and cardiovascular phenotypic spectrum in a Chinese cohort of Loeys-Dietz syndrome patients. Orphanet J Rare Dis. 2020 Jan 8;15(1):6. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D;.;.;.
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	H;.;.;.
PhyloP100		10
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-8.8	D;D;D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.99
MutPred		0.95		Loss of disorder (P = 0.0621);.;.;.;
MVP		0.97
MPC		1.9
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.99
gMVP		0.96
Mutation Taster		=1/99	disease causing

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

Other links and lift over

dbSNP: rs869025535; hg19: chr9-101904947; COSMIC: COSV66625357; COSMIC: COSV66625357;