rs796051885
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PM5PP3_ModeratePP5_Very_Strong
The NM_003239.5(TGFB3):c.898C>T(p.Arg300Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,852 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. R300Q) has been classified as Pathogenic.
Frequency
Consequence
NM_003239.5 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 |
---|---|---|---|---|---|---|---|
TGFB3 | NM_003239.5 | c.898C>T | p.Arg300Trp | missense_variant | 5/7 | ENST00000238682.8 | |
TGFB3 | NM_001329939.2 | c.898C>T | p.Arg300Trp | missense_variant | 6/8 | ||
TGFB3 | NM_001329938.2 | c.898C>T | p.Arg300Trp | missense_variant | 5/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TGFB3 | ENST00000238682.8 | c.898C>T | p.Arg300Trp | missense_variant | 5/7 | 1 | NM_003239.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461852Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2AN XY: 727218
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Nov 10, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 27, 2022 | Not observed 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: 25835445, 31898322, 27848944, 29392890) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Jul 13, 2018 | - - |
Familial thoracic aortic aneurysm and aortic dissection Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Dec 04, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 13, 2018 | The p.R300W pathogenic mutation (also known as c.898C>T), located in coding exon 5 of the TGFB3 gene, results from a C to T substitution at nucleotide position 898. The arginine at codon 300 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration is located in the latency-associated peptide domain and has been reported in individuals and families with hypertelorism, bifid uvula and/or cleft palate, and other overlapping Loeys-Dietz and Marfan syndrome-like features (Bertoli-Avella AM et al. J. Am. Coll. Cardiol., 2015 Apr;65:1324-36; Trujillano D et al. Eur. J. Hum. Genet., 2017 02;25:176-182; Schepers D et al. Hum. Mutat., 2018 May;39:621-634). Other substitutions at this amino acid position, p.R300Q and p.R300G, have been identified in families with similar clinical findings, as well as in an affected individual reported as a de novo case (Matyas G et al. Am. J. Med. Genet. A, 2014 Aug;164A:2141-3; Kuechler A et al. Mol. Cell. Probes, 2015 Oct;29:330-4). Internal structural analysis indicates that alterations at this position disrupt the putative furin pro-peptide cleavage motif of the protein (Dubois CM et al. J. Biol. Chem., 1995 May;270:10618-24; Lafyatis R. Nat Rev Rheumatol, 2014 Dec;10:706-19; Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Rienhoff syndrome Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 07, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 17, 2023 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 300 of the TGFB3 protein (p.Arg300Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Loeys-Dietz syndrome (PMID: 25835445, 31898322). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 203490). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TGFB3 protein function. This variant disrupts the p.Arg300 amino acid residue in TGFB3. Other variant(s) that disrupt this residue have been observed in individuals with TGFB3-related conditions (PMID: 24798638, 26184463), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at