chr1-218436110-C-T
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PM5PP3_ModeratePP5_Very_Strong
The NM_003238.6(TGFB2):c.895C>T(p.Arg299Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,422 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R299Q) has been classified as Likely pathogenic.
Frequency
Consequence
NM_003238.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TGFB2 | NM_003238.6 | c.895C>T | p.Arg299Trp | missense_variant | 5/7 | ENST00000366930.9 | |
TGFB2 | NM_001135599.4 | c.979C>T | p.Arg327Trp | missense_variant | 6/8 | ||
TGFB2 | NR_138148.2 | n.2146C>T | non_coding_transcript_exon_variant | 5/7 | |||
TGFB2 | NR_138149.2 | n.2230C>T | non_coding_transcript_exon_variant | 6/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TGFB2 | ENST00000366930.9 | c.895C>T | p.Arg299Trp | missense_variant | 5/7 | 1 | NM_003238.6 | P1 | |
TGFB2 | ENST00000366929.4 | c.979C>T | p.Arg327Trp | missense_variant | 6/8 | 1 | |||
TGFB2 | ENST00000479322.1 | n.379C>T | non_coding_transcript_exon_variant | 3/5 | 3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461422Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 726984
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Loeys-Dietz syndrome 4 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Nov 15, 2019 | The c.979C>T variant in the TGFB2 gene results in an amino acid change at residue 327 from an arginine to a tryptophan in the resultant protein (p.Arg327Trp). Also known as c.895C>T (p.Arg299Trp) using an alternate transcript, this variant has been reported in multiple individuals with Loeys-Dietz syndrome and thoracic aortic aneurysms and dissections (PMID: 22772368, 26854089, 23102774). This variant is located in RKKR-motif, an important protein domain where other pathogenic variants have been described. Another variant at this same amino acid position (p.Arg299Gln) has also been reported in association with aortic aneurysms and dissections (PMID: 23102774, 25644172). Multiple lines of in-silico algorithms predict this change to be deleterious. In addition, this variant is absent from population databases (gnomAD). We consider this variant to be pathogenic. - |
Pathogenic, criteria provided, single submitter | research | Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 04, 2023 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 299 of the TGFB2 protein (p.Arg299Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Loeys-Dietz syndrome and syndromic thoracic aortic aneurysms and dissections (PMID: 22772368, 23102774, 26854089). It has also been observed to segregate with disease in related individuals. This variant is also known as c.979C>T (p.Arg327Trp). ClinVar contains an entry for this variant (Variation ID: 213845). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TGFB2 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 25, 2022 | Not observed in large population cohorts (gnomAD); Located in the RKKR motif, where a significant number of missense variants have been reported in association with LDS to date (Schepers et al., 2018); 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: 22772368, 26854089, 31191903, 33125268, 29907982, 29392890) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 07, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2021 | - - |
Familial aortopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 06, 2020 | Variant summary: TGFB2 c.895C>T (p.Arg299Trp) results in a non-conservative amino acid change located in the C-terminal domain (IPR001839) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250514 control chromosomes (gnomAD). The variant, c.895C>T (also known asc.979C>T (p.Arg327Trp) in the literature), has been reported in the literature in multiple individuals and families affected with Aortopathy, and has been observed to segregate with the disease in at least two families (e.g. Lindsay_2012, Schubert_2016, Bashari_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as likely pathogenic (2x) or pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 14, 2023 | The p.R299W variant (also known as c.895C>T), located in coding exon 5 of the TGFB2 gene, results from a C to T substitution at nucleotide position 895. The arginine at codon 299 is replaced by tryptophan, an amino acid with dissimilar properties. This variant (described as NM_001135599.2:c.979C>T, p.R327W) has been reported in multiple affected individuals with Loeys-Dietz syndrome or syndromic thoracic aortic aneurysm findings; co-segregation was also reported in some affected relatives (Lindsay ME et al. Nat. Genet., 2012 Jul;44:922-7; Renard M et al. Int. J. Cardiol., 2013 May;165:584-7; Schubert JA et al. Am. J. Med. Genet. A, 2016 May;170A:1288-94; Overwater E et al. Hum. Mutat., 2018 09;39:1173-1192; Bashari H et al. SAGE Open Med Case Rep, 2019 May;7:2050313X19852539). A different variant affecting this codon, p.R299Q, c.896G>A (also referred to as p.R327Q, c.980G>A) has been reported in association with syndromic thoracic aortic aneurysm findings (Renard M et al. Int. J. Cardiol., 2013 May;165:584-7; Campens L et al. Orphanet J Rare Dis, 2015 Feb;10:9). 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 majority of available evidence to date, this variant is likely to be pathogenic. - |
TGFB2-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 09, 2022 | The TGFB2 c.895C>T variant is predicted to result in the amino acid substitution p.Arg299Trp. This variant, also known as p.Arg327Trp in the literature, was reported in multiple individuals with Loeys-Dietz syndrome presenting thoracic aortic aneurysms and dissections or coronary artery dissections (Lindsay et al. 2012. PubMed ID: 22772368; Schubert et al. 2016. PubMed ID: 26854089; Overwater et al. 2018. PubMed ID: 29907982; Bashari et al. 2019. PubMed ID: 31191903; Carss et al. 2020. PubMed ID: 33125268). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at