rs137854466
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PS3PS4PP1_StrongPVS1_StrongPP4PM2_Supporting
This summary comes from the ClinGen Evidence Repository: The NM_00138 c.8326C>T, is a nonsense variant in FBN1 that occurs in the last exon of the gene and is not expected to undergo nonsense-mediated decay but is expected to disrupt the last 96 amino acids of the protein. Premature terminations in the C-terminus are considered to be deleterious (PVS1_Strong; PMID 24982166, 12161601, 7911051, 21034599). In an in-vitro microfibril assay, this variant was reported to result in intracellular retention of the protein (PMID 24982166; PS3). This variant was found in a proband with aortic aneurysm and dissection, ectopia lentis, and skeletal features, who met revised Ghent criteria, which is a highly specific phenotype for Marfan syndrome (MFS) (Internal lab data; PP4). This variant has been reported 10 times in ClinVar, nine as pathogenic and once as likely pathogenic (Variation ID: 16439). Several other probands with a clinical diagnosis of Marfan syndrome and/or clinical features of Marfan syndrome carry the same variant (internal lab data, PMID 9338581, 31098894, 31730815, 33059708, 25907466, 19293843, 34916231; PS4). In one individual with aortic dissection and myopia, this variant was reported to be de novo without confirmation of parental relationships (PMID 31098894; 0.25 points). In two families with MFS, this variant was found to segregate with disease in five affected family members (internal lab data; PP1_Strong). This variant is present in in 10/24982 (0.04%) of alleles tested from the Finnish population in gnomAD and did not pass the quality control criteria in the genome subset (PM2_Sup; https://gnomad.broadinstitute.org/ v2.1.1). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PVS1_Strong, PS4, PS3, PP1_Strong, PM2_Sup, PP4 LINK:https://erepo.genome.network/evrepo/ui/classification/CA017692/MONDO:0007947/022
Frequency
Consequence
NM_000138.5 stop_gained
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152114Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000398 AC: 10AN: 251286Hom.: 0 AF XY: 0.0000737 AC XY: 10AN XY: 135772
GnomAD4 exome AF: 0.0000123 AC: 18AN: 1461668Hom.: 0 Cov.: 31 AF XY: 0.0000248 AC XY: 18AN XY: 727076
GnomAD4 genome 0.00000657 AC: 1AN: 152232Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74430
ClinVar
Submissions by phenotype
Marfan syndrome Pathogenic:6Uncertain:1
- -
At our clinical center The p.R2776* variant was found in one family and one unrelated individual. This variant present in variouas individual studies reported by other submitters (ClinVar entry - Variation ID:16439), as well as present in population studies (C=0.00001 (1/121406, ExAC)). Functional study of the variant (PMID: 24982166) shows its pathogenic mechanism by linkage of the immature monomers, thus it behaves as a dominant-negative mutation, disrupting not only the mutant protein, but the normal one, which is synthesized from the unchanged allele. -
- -
The NM_00138 c.8326C>T, is a nonsense variant in FBN1 that occurs in the last exon of the gene and is not expected to undergo nonsense-mediated decay but is expected to disrupt the last 96 amino acids of the protein. Premature terminations in the C-terminus are considered to be deleterious (PVS1_Strong; PMID 24982166, 12161601, 7911051, 21034599). In an in-vitro microfibril assay, this variant was reported to result in intracellular retention of the protein (PMID 24982166; PS3). This variant was found in a proband with aortic aneurysm and dissection, ectopia lentis, and skeletal features, who met revised Ghent criteria, which is a highly specific phenotype for Marfan syndrome (MFS) (Internal lab data; PP4). This variant has been reported 10 times in ClinVar, nine as pathogenic and once as likely pathogenic (Variation ID: 16439). Several other probands with a clinical diagnosis of Marfan syndrome and/or clinical features of Marfan syndrome carry the same variant (internal lab data, PMID 9338581, 31098894, 31730815, 33059708, 25907466, 19293843, 34916231; PS4). In one individual with aortic dissection and myopia, this variant was reported to be de novo without confirmation of parental relationships (PMID 31098894; 0.25 points). In two families with MFS, this variant was found to segregate with disease in five affected family members (internal lab data; PP1_Strong). This variant is present in in 10/24982 (0.04%) of alleles tested from the Finnish population in gnomAD and did not pass the quality control criteria in the genome subset (PM2_Sup; https://gnomad.broadinstitute.org/ v2.1.1). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PVS1_Strong, PS4, PS3, PP1_Strong, PM2_Sup, PP4 -
PVS1, PP3, PP5 -
- -
PS4, PS1, PP4 or PS4, PS1, PP1, PP4 -
not provided Pathogenic:2
Functional studies suggest that the variant results in intra-cellular retention of the protein (Jensen et al., 2014); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 96 amino acid residues are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database and published literature (HGMD; Lonnqvist et al., 1998; Ritty et al., 1999; Jensen et al., 2014); This variant is associated with the following publications: (PMID: 9817919, 10085138, 11826022, 24982166, 7911051, 10756346, 19293843, 33059708, 33824467, 31098894, 9338581, 31730815, 34008892) -
- -
Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
The p.R2776* pathogenic mutation (also known as c.8326C>T), located in coding exon 65 of the FBN1 gene, results from a C to T substitution at nucleotide position 8326. This changes the amino acid from an arginine to a stop codon within coding exon 65. This alteration occurs at the 3' terminus of theFBN1 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 96 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This alteration, which is also known as p.R1878*, c.5632C>T, has been reported in multiple individuals with Marfan syndrome (Hayward C et al. Hum. Mutat., 1994;3:159-62; Körkkö J et al. J. Med. Genet., 2002 Jan;39:34-41; Stheneur C et al. Eur J Hum Genet, 2009 Sep;17:1121-8; Jensen SA et al. Proc Natl Acad Sci U S A, 2014 Jul;111:10155-60; Proost D et al. Hum Mutat, 2015 Aug;36:808-14; Li J et al. Sci China Life Sci, 2019 Dec;62:1630-1637; Mannucci L et al. Clin Chim Acta, 2020 Feb;501:154-164; Stengl R et al. Orphanet J Rare Dis, 2020 10;15:290). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Isolated thoracic aortic aneurysm Pathogenic:1
- -
Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
This sequence change creates a premature translational stop signal (p.Arg2776*) in the FBN1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 96 amino acid(s) of the FBN1 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with FBN-1 related conditions (PMID: 7911051, 9338581, 11826022). ClinVar contains an entry for this variant (Variation ID: 16439). This variant disrupts a region of the FBN1 protein in which other variant(s) (p.Leu2854Profs*9, p.Gln2830*, p.Leu2854Profs*9) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at