rs727504292
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM5PP5
The NM_003242.6(TGFBR2):c.1067G>A(p.Arg356Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000225 in 1,603,034 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R356G) has been classified as Likely pathogenic.
Frequency
Consequence
NM_003242.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TGFBR2 | NM_003242.6 | c.1067G>A | p.Arg356Gln | missense_variant | 4/7 | ENST00000295754.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TGFBR2 | ENST00000295754.10 | c.1067G>A | p.Arg356Gln | missense_variant | 4/7 | 1 | NM_003242.6 | P1 | |
TGFBR2 | ENST00000359013.4 | c.1142G>A | p.Arg381Gln | missense_variant | 5/8 | 1 | |||
TGFBR2 | ENST00000672866.1 | n.2663G>A | non_coding_transcript_exon_variant | 4/7 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152210Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000164 AC: 4AN: 243902Hom.: 0 AF XY: 0.0000152 AC XY: 2AN XY: 131396
GnomAD4 exome AF: 0.0000234 AC: 34AN: 1450824Hom.: 0 Cov.: 34 AF XY: 0.0000236 AC XY: 17AN XY: 720178
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152210Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74358
ClinVar
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jul 08, 2022 | This missense variant replaces arginine with glutamine at codon 356 of the TGFBR2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 5/275296 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg356Pro, is known to be pathogenic (Clinvar variation ID 177704), indicating that arginine at this position is important for TGFBR2 protein function. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 26, 2021 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 356 of the TGFBR2 protein (p.Arg356Gln). This variant is present in population databases (rs727504292, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with TGFBR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 919773). 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 not expected to disrupt TGFBR2 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Arg356 amino acid residue in TGFBR2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16283890, 16835936, 22095581, 24220024, 27611364). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 24, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 35535697) - |
Loeys-Dietz syndrome 2 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | Laan Lab, Human Genetics Research Group, University of Tartu | May 01, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at