rs774003646
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP2BS4
This summary comes from the ClinGen Evidence Repository: NM_00138 c.3689T>C is a missense variant in FBN1 predicted to cause a substitution of a Methionine by Threonine at amino acid 1230 p.(Met1230Thr). This variant was identified in an internal proband with ectopia lentis and thoracic aortic aneurysm and dissection, however a pathogenic frameshift variant in FBN1 was also identified in the proband (BP2) and was considered to explain the phenotype. Furthermore this variant does not segregate with disease in an affected family member (BS4). . This variant has been previously reported in ClinVar as of uncertain significance (Variation ID: 263789). This variant has been identified in 0.0018% of individuals of European origin (https://gnomad.broadinstitute.org/). Computational prediction tools and conservation analysis are unclear on the predicted impact on the protein. The constraint z-score for missense variants affecting FBN1 is 5.06 however due to the presence of one benign argument PP2 cannot be used . In summary, this variant meets criteria to be classified as likely benign for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: BS4, BP2 LINK:https://erepo.genome.network/evrepo/ui/classification/CA051349/MONDO:0007947/022
Frequency
Consequence
NM_000138.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FBN1 | NM_000138.5 | c.3689T>C | p.Met1230Thr | missense_variant | 30/66 | ENST00000316623.10 | |
FBN1 | NM_001406716.1 | c.3689T>C | p.Met1230Thr | missense_variant | 29/65 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBN1 | ENST00000316623.10 | c.3689T>C | p.Met1230Thr | missense_variant | 30/66 | 1 | NM_000138.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251480Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135912
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461878Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727244
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 26, 2017 | The p.M1230T variant (also known as c.3689T>C), located in coding exon 29 of the FBN1 gene, results from a T to C substitution at nucleotide position 3689. The methionine at codon 1230 is replaced by threonine, an amino acid with some similar properties. This amino acid position is well 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 16, 2023 | This missense variant replaces methionine with threonine at codon 1230 of the FBN1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with FBN1-related disorders in the literature. This variant has been identified in 2/251480 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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. - |
Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 20, 2023 | 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. 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 FBN1 protein function. ClinVar contains an entry for this variant (Variation ID: 263789). This variant has not been reported in the literature in individuals affected with FBN1-related conditions. This variant is present in population databases (rs774003646, gnomAD 0.002%). This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1230 of the FBN1 protein (p.Met1230Thr). - |
Marfan syndrome Benign:1
Likely benign, reviewed by expert panel | curation | ClinGen FBN1 Variant Curation Expert Panel, ClinGen | Dec 01, 2022 | NM_00138 c.3689T>C is a missense variant in FBN1 predicted to cause a substitution of a Methionine by Threonine at amino acid 1230 p.(Met1230Thr). This variant was identified in an internal proband with ectopia lentis and thoracic aortic aneurysm and dissection, however a pathogenic frameshift variant in FBN1 was also identified in the proband (BP2) and was considered to explain the phenotype. Furthermore this variant does not segregate with disease in an affected family member (BS4). . This variant has been previously reported in ClinVar as of uncertain significance (Variation ID: 263789). This variant has been identified in 0.0018% of individuals of European origin (https://gnomad.broadinstitute.org/). Computational prediction tools and conservation analysis are unclear on the predicted impact on the protein. The constraint z-score for missense variants affecting FBN1 is 5.06 however due to the presence of one benign argument PP2 cannot be used . In summary, this variant meets criteria to be classified as likely benign for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: BS4, BP2 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at