rs760079636

Variant names:

• chr9-99142664-G-A
• rs760079636
• NM_004612.4:c.934G>A

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_004612.4(TGFBR1):​c.934G>A​(p.Gly312Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TGFBR1 NM_004612.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 10.0

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 Pathogenic. Variant got 17 ACMG points.

• PM1: In a domain Protein kinase (size 290) in uniprot entity TGFR1_HUMAN there are 34 pathogenic changes around while only 2 benign (94%) 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, 0.991
• PP5: Variant 9-99142664-G-A is Pathogenic according to our data. Variant chr9-99142664-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 213882.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBR1	NM_004612.4	c.934G>A	p.Gly312Ser	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.934G>A	p.Gly312Ser	missense_variant	Exon 5 of 9	1	NM_004612.4	ENSP00000364133.4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251070 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135662

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461768 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727192

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: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152126 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74294

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:3

Nov 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 312 of the TGFBR1 protein (p.Gly312Ser). This variant is present in population databases (rs760079636, gnomAD 0.004%). This missense change has been observed in individuals with thoracic aortic aneurysm and dissection and/or clinical features of Loeys-Dietz syndrome (PMID: 16799921, 19542084, 26848186, 26877057, 30739908). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 213882). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt TGFBR1 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Feb 27, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G312S variant (also known as c.934G>A), located in coding exon 5 of the TGFBR1 gene, results from a G to A substitution at nucleotide position 934. The glycine at codon 312 is replaced by serine, an amino acid with similar properties. This variant was reported in multiple individuals with features consistent with Loeys-Dietz syndrome, and was reported to segregate with disease features in families (Singh KK et al. Hum. Mutat., 2006 Aug;27:770-7; Luo M et al. Clin. Chim. Acta, 2016 May;456:144-8;Teixidó-Tura G et al. Heart, 2016 Apr;102:626-32; Tran-Fadulu V et al. J. Med. Genet., 2009 Sep;46:607-13; Nickol JL et al. Eur Heart J Case Rep. 2022 Oct;6(10):ytac383). Internal structural analysis indicates that G312 resides in the protein kinase domain and this variant would disrupt the protein structure (Huse M et al. Cell. 1999 Feb;96(3):425-36; Ambry internal data). This variant is considered to be rare based on population 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 supporting evidence, this alteration is likely to be pathogenic for Loeys-Dietz syndrome; however, the association of this alteration with susceptibility to multiple self-healing squamous epithelioma is unknown. -

Jun 22, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glycine with serine at codon 312 of the TGFBR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with Marfan syndrome with a family history of thoracic aortic aneurysm and dissection (PMID: 16799921) and in over 15 individuals affected with thoracic aortic aneurysm and dissection, including three related individuals (PMID: 19542084, 27879313, 30739908). This variant has also been identified in four individuals affected with Loeys-Dietz syndrome (PMID: 26877057, 26848186, 31915033, 36237225). This variant has been identified in 1/251070 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

not provided Pathogenic:3

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TGFBR1: PM1, PM2, PP3, PS4:Supporting -

Feb 23, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TGFBR1 c.934G>A; p.Gly312Ser variant (rs760079636) is reported in the literature in numerous individuals affected with symptoms of an aortopathy disorder and has been reported to segregate with disease in several small kindreds (Arnaud 2019, Jondeau 2016, Luo 2016, Nickol 2022, Singh 2006, Tran-Fadulu 2009, Yang 2020). This variant is only observed on one allele in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.964). Based on available information, this variant is considered to be likely pathogenic. References: Arnaud et al. Genetic diversity and pathogenic variants as possible predictors of severity in a French sample of nonsyndromic heritable thoracic aortic aneurysms and dissections (nshTAAD). Genet Med. 2019 Sep;21(9):2015-2024. PMID: 30739908. Jondeau G et al. International Registry of Patients Carrying TGFBR1 or TGFBR2 Mutations: Results of the MAC (Montalcino Aortic Consortium). Circ Cardiovasc Genet. 2016 Dec;9(6):548-558. PMID: 27879313. Luo M et al. Genetic testing of 10 patients with features of Loeys-Dietz syndrome. Clin Chim Acta. 2016 May 1;456:144-148. PMID: 26877057. Nickol JL et al. Case report of Loeys-Dietz syndrome presenting with coronary artery aneurysm. Eur Heart J Case Rep. 2022 Sep 15;6(10):ytac383. PMID: 36237225. 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. PMID: 16799921. Tran-Fadulu V et al. Analysis of multigenerational families with thoracic aortic aneurysms and dissections due to TGFBR1 or TGFBR2 mutations. J Med Genet. 2009 Sep;46(9):607-13. PMID: 19542084. 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. PMID: 31915033. -

May 23, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 31915033, 26877057, 26848186, 17061023, 30739908, 16799921, 19542084, 27879313, 36237225) -

Loeys-Dietz syndrome Pathogenic:2

Dec 18, 2023

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glycine with serine at codon 312 of the TGFBR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with Marfan syndrome with a family history of thoracic aortic aneurysm and dissection (PMID: 16799921) and in over 15 individuals affected with thoracic aortic aneurysm and dissection, including three related individuals (PMID: 19542084, 27879313, 30739908). This variant has also been identified in four individuals affected with Loeys-Dietz syndrome (PMID: 26877057, 26848186, 31915033, 36237225). This variant has been identified in 1/251070 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Apr 07, 2015

Blueprint Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial aortopathy Pathogenic:1

May 08, 2023

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TGFBR1 c.934G>A (p.Gly312Ser) results in a non-conservative amino acid change located in the protein kinase domain (IPR000719) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251070 control chromosomes (gnomAD). c.934G>A has been reported in the literature in multiple individuals affected with Aortopathy, including patients and families with Loeys-Dietz Syndrome and TAAD, with strong segregation data (e.g. Luo_2016, Singh_2006, Teixido-Tura_2016, Tran-Fadulu_2009). These data indicate that the variant is very likely to be associated with disease. Additionally, the Montalcino Aortic Consortium reports the variant in 14 patients from an international registry, and showed the variant to have significantly poorer survival without aortic event (dissection or surgery) compared to patients with any other TGFRB1 mutations (Jondeau_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27879313, 26877057, 16799921, 26848186, 19542084, 31915033). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=1)/likely pathogenic (n=5). Based on the evidence outlined above, the variant was classified as pathogenic. -

Multiple self-healing squamous epithelioma;C4551955:Loeys-Dietz syndrome 1 Pathogenic:1

Feb 01, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Loeys-Dietz syndrome 1 Pathogenic:1

Apr 29, 2022

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

_x000D_ Criteria applied: PS4, PM2_SUP, PP3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.51	D;.;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D;D;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	H;.;.;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.8	D;D;D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.91
MutPred		0.96		Gain of disorder (P = 0.0521);.;.;.;
MVP		0.98
MPC		1.7
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.97
gMVP		0.92

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: rs760079636; hg19: chr9-101904946;