9-99137963-G-A
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP2PP3PP5
The NM_004612.4(TGFBR1):c.679G>A(p.Glu227Lys) 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_004612.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1Uncertain:1
The p.E227K variant (also known as c.679G>A), located in coding exon 4 of the TGFBR1 gene, results from a G to A substitution at nucleotide position 679. The glutamic acid at codon 227 is replaced by lysine, an amino acid with similar properties, and is located in the protein kinase domain. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 227 of the TGFBR1 protein (p.Glu227Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with aortic dissection (Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 408566). 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 TGFBR1 protein function. For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:1
p.Glu227Lys (c.679G>A) in the TGFBR1 gene (NM_004612.2) The lab classifies this variant as a variant of unknown significance. Given the patient's phenotype is consistent with Loeys-Dietz syndrome and there is lack of variation at this position in the general population and through evolution we consider this variant likely disease causing. This variant was not inherited from the patient's father and was likely inherited by the patient's mother who passed from an aortic dissection at 4.5 cm (at the AoSV) which indicates that she likely had Loeys-Dietz syndrome given her relatively small aortic diameter at the time of dissection. The variant is novel in this family. One of the patient's sisters who has hypermobility and a long uvula also tested positive for this variant. Cardiac evaluation is pending. In silico analysis with PolyPhen-2 predicts the variant to be pathogenic (HumVar: 0.998) and mutation taster agrees (0.999). The glutamic acid at codon 227 is conserved across species, as are neighboring amino acids. This variant is located in the catalytic kinase domain of the extracellular protein component and likely inhibits binding through the catalytic kinase domain. Other variants in this domain have been shown to be pathogenic. There is no variation at codon 227 listed in the Genome Aggregation database (http://gnomad.broadinstitute.org/), which currently includes variant calls on ~140,000 individuals of European, African, Latino and Asian descent (as of Jan 31, 2017) indicating that variation at this position is extremely rare. There is no variation listed in the gnomad database between codons 223 and 233 indicating that this area of the protein is not tolerant of missense variation and likely disrupts protein function. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at