rs2228241
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS1BS4
This summary comes from the ClinGen Evidence Repository: NM_00138 c.3422C>T is a missense variant in FBN1 predicted to cause a substitution of a Proline by Leucine at amino acid 1141 (p.Pro1141Leu). This variant has been reported in the literature in at least 3 individuals in association with thoracic aortic aneurysm and dissection (TAAD), MASS syndrome, and features possibly consistent with Marfan syndrome (PMID:10533071; PMID:24740214; PMID:26188975). This variant was also identified in an internal proband with isolated TAAD with a family history highly specific for Marfan syndrome, however it does not segregate with disease in an affected family member (BS4) and therefore PP4 cannot be used. This variant has been previously reported in ClinVar as benign, likely benign, and uncertain significance (Variation ID: 42334). This variant has been identified in 0.026% of individuals of European origin (BS1; https://gnomad.broadinstitute.org/ version 2.1.1). 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 two benign arguments PP2 cannot be used. In summary, this variant meets criteria to be classified as benign for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: BS1, BS4 LINK:https://erepo.genome.network/evrepo/ui/classification/CA014098/MONDO:0007947/022
Frequency
Consequence
NM_000138.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FBN1 | NM_000138.5 | c.3422C>T | p.Pro1141Leu | missense_variant | 28/66 | ENST00000316623.10 | |
FBN1 | NM_001406716.1 | c.3422C>T | p.Pro1141Leu | missense_variant | 27/65 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBN1 | ENST00000316623.10 | c.3422C>T | p.Pro1141Leu | missense_variant | 28/66 | 1 | NM_000138.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000572 AC: 87AN: 152192Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000903 AC: 227AN: 251480Hom.: 1 AF XY: 0.000846 AC XY: 115AN XY: 135914
GnomAD4 exome AF: 0.000508 AC: 742AN: 1461884Hom.: 4 Cov.: 32 AF XY: 0.000527 AC XY: 383AN XY: 727244
GnomAD4 genome ? AF: 0.000571 AC: 87AN: 152310Hom.: 0 Cov.: 32 AF XY: 0.000497 AC XY: 37AN XY: 74476
ClinVar
Submissions by phenotype
Marfan syndrome Uncertain:1Benign:3
Benign, reviewed by expert panel | curation | ClinGen FBN1 Variant Curation Expert Panel, ClinGen | Dec 01, 2022 | NM_00138 c.3422C>T is a missense variant in FBN1 predicted to cause a substitution of a Proline by Leucine at amino acid 1141 (p.Pro1141Leu). This variant has been reported in the literature in at least 3 individuals in association with thoracic aortic aneurysm and dissection (TAAD), MASS syndrome, and features possibly consistent with Marfan syndrome (PMID: 10533071; PMID: 24740214; PMID: 26188975). This variant was also identified in an internal proband with isolated TAAD with a family history highly specific for Marfan syndrome, however it does not segregate with disease in an affected family member (BS4) and therefore PP4 cannot be used. This variant has been previously reported in ClinVar as benign, likely benign, and uncertain significance (Variation ID: 42334). This variant has been identified in 0.026% of individuals of European origin (BS1; https://gnomad.broadinstitute.org/ version 2.1.1). 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 two benign arguments PP2 cannot be used. In summary, this variant meets criteria to be classified as benign for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: BS1, BS4 - |
Uncertain significance, no assertion criteria provided | clinical testing | Center for Medical Genetics Ghent, University of Ghent | Nov 07, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Center for Human Genetics, Inc, Center for Human Genetics, Inc | Nov 01, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | May 01, 2019 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Familial thoracic aortic aneurysm and aortic dissection Benign:4
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 24, 2016 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 11, 2018 | - - |
Benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Sep 05, 2019 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | May 01, 2019 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | FBN1: BS1, BS2 - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 29, 2020 | This variant is associated with the following publications: (PMID: 25812041, 26188975, 10533071, 24941995, 24740214, 27153395, 25203624) - |
Developmental cataract Uncertain:1
Uncertain significance, no assertion criteria provided | research | Dept. Genetics and Cancer, Menzies Institute for Medical Research, University of Tasmania | May 01, 2021 | - - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 02, 2019 | The p.Pro1141Leu variant in FBN1 is classified as benign because it has been ide ntified in 1.8% of Ashkenazi Jewish chromosomes by gnomAD. ACMG/AMP Criteria app lied: BA1. - |
Stiff skin syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | May 01, 2019 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Weill-Marchesani syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | May 01, 2019 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Geleophysic dysplasia Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | May 01, 2019 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Acromicric dysplasia Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | May 01, 2019 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | - - |
Ectopia lentis 1, isolated, autosomal dominant Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | May 01, 2019 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at