chr3-30672246-G-C
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_003242.6(TGFBR2):c.1063G>C(p.Ala355Pro) variant causes a missense change. 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. A355T) has been classified as Uncertain significance.
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.1063G>C | p.Ala355Pro | missense_variant | 4/7 | ENST00000295754.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TGFBR2 | ENST00000295754.10 | c.1063G>C | p.Ala355Pro | missense_variant | 4/7 | 1 | NM_003242.6 | P1 | |
TGFBR2 | ENST00000359013.4 | c.1138G>C | p.Ala380Pro | missense_variant | 5/8 | 1 | |||
TGFBR2 | ENST00000672866.1 | n.2659G>C | non_coding_transcript_exon_variant | 4/7 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 34
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 12, 2021 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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 TGFBR2 protein function. This variant has been observed in individual(s) with clinical features of TGFBR2-related conditions (PMID: 15731757, Invitae). ClinVar contains an entry for this variant (Variation ID: 12509). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with proline at codon 355 of the TGFBR2 protein (p.Ala355Pro). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and proline. - |
Loeys-Dietz syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 24, 2019 | Variant summary: TGFBR2 c.1063G>C (p.Ala355Pro) results in a non-conservative amino acid change located in the Serine-threonine/tyrosine-protein kinase, catalytic domain (IPR001245) 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 245344 control chromosomes (gnomAD and Loeys_2005). c.1063G>C has been reported in the literature in individuals affected with Loeys-Dietz Syndrome (Loeys_2005). These data indicate that the variant may be associated with disease. One study demonstrated intracellular accumulation of collagen type I in fibroblasts collected from the patient carrying this variant (Barnett_2011). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Loeys-Dietz syndrome 2 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2005 | - - |
Colorectal cancer, hereditary nonpolyposis, type 6 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Dec 10, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at