chr3-30691475-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP3_ModeratePP5
The NM_003242.6(TGFBR2):c.1580C>T(p.Ala527Val) 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A527T) has been classified as Likely pathogenic.
Frequency
Consequence
NM_003242.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TGFBR2 | NM_003242.6 | c.1580C>T | p.Ala527Val | missense_variant | 7/7 | ENST00000295754.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TGFBR2 | ENST00000295754.10 | c.1580C>T | p.Ala527Val | missense_variant | 7/7 | 1 | NM_003242.6 | P1 |
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:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 26, 2018 | The p.A527V variant (also known as c.1580C>T), located in coding exon 7 of the TGFBR2 gene, results from a C to T substitution at nucleotide position 1580. The alanine at codon 527 is replaced by valine, an amino acid with similar properties, and is located in the cbEGF-like #03 domain. This alteration has been reported in an individual with Loeys-Dietz syndrome (LDS) (Loeys BL et al. N. Engl. J. Med., 2006 Aug;355:788-98). An alternate substitution at this position, p.A527T (c.1579G>A), has also been associated with LDS (Poninska JK et al. J Transl Med, 2016 May;14:115). The current alteration and the close match, p.A527T, have both been reported in a LDS cohort, but limited clinical details were provided (Frischmeyer-Guerrerio PA et al. Sci Transl Med, 2013 Jul;5:195ra94). 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 24, 2023 | This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 527 of the TGFBR2 protein (p.Ala527Val). This missense change has been observed in individuals with TGFBR2-related disease (PMID: 16928994, 18852674; Invitae). ClinVar contains an entry for this variant (Variation ID: 165398). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt TGFBR2 function. This variant disrupts the p.Ala527 amino acid residue in TGFBR2. Other variant(s) that disrupt this residue have been observed in individuals with TGFBR2-related conditions (PMID: 27146836, 27508510), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. - |
Loeys-Dietz syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 07, 2016 | Variant summary: The TGFBR2 c.1580C>T (p.Ala527Val) variant involves the alteration of a highly conserved nucleotide and is located in the protein kinase domain of the protein (InterPro, UniProt). The alanine residue at this codon is highly conserved across species, and 4/4 in silico tools predict a damaging outcome for this variant. This variant was absent in 121254 control chromosomes from the broad and large populations of ExAC. In the literature, this variant was reported as a pathogenic variant found in three patients with Loeys-Dietz syndrome (Loeys_2006, Frischmeyer-Guerrerio_2013). Another missense change at the same residue, p.Ala527Thr, has also been reported in patients with Loeys-Dietz syndrome (Frischmeyer-Guerrerio_2013, Poninska_ J Transl Med_2016). In addition, several other potentially/likely pathogenic variants, such as p.Asp524Asn, p.Glu526Gln, p.Arg528Cys, p.Arg528His, and p.Ala531Thr have also been reported in this region, suggesting the region is mutational hot-spot. Furthermore, one reputable database has classified it as disease-causing. Taken together, this variant is currently classified as Likely Pathogenic. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 15, 2022 | 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: 23884466, 27508510, 27146836, 18852674, 16928994, 17061023) - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 15, 2011 | Variant classified as Uncertain Significance - Favor Pathogenic. The Ala527Val v ariant has been previously reported in 1 individual with clinical features of Lo eys-Dietz syndrome and was absent from 200 control chromosomes (Loeys 2006). Ala nine (Ala) at position 527 is highly conserved across evolutionarily distant spe cies, increasing the likelihood that the change is pathogenic. However, computer predictions are mixed (AlignGVGD = benign, Polyphen2 & SIFT = pathogenic), thou gh these tools have not been validated sufficiently to assume pathogenicity. Alt hough these data suggests that the Ala527Val variant may be disease causing, add itional information is required to fully assess this variant. Therefore, the cli nical significance of this variant cannot be determined at this time. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at