15-48494209-C-T
Position:
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_000138.5(FBN1):c.2723G>A(p.Cys908Tyr) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C908R) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 33)
Consequence
FBN1
NM_000138.5 missense
NM_000138.5 missense
Scores
13
2
2
Clinical Significance
Conservation
PhyloP100: 7.12
Genes affected
FBN1 (HGNC:3603): (fibrillin 1) This gene encodes a member of the fibrillin family of proteins. The encoded preproprotein is proteolytically processed to generate two proteins including the extracellular matrix component fibrillin-1 and the protein hormone asprosin. Fibrillin-1 is an extracellular matrix glycoprotein that serves as a structural component of calcium-binding microfibrils. These microfibrils provide force-bearing structural support in elastic and nonelastic connective tissue throughout the body. Asprosin, secreted by white adipose tissue, has been shown to regulate glucose homeostasis. Mutations in this gene are associated with Marfan syndrome and the related MASS phenotype, as well as ectopia lentis syndrome, Weill-Marchesani syndrome, Shprintzen-Goldberg syndrome and neonatal progeroid syndrome. [provided by RefSeq, Apr 2016]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 17 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr15-48494210-A-G is described in Lovd as [Likely_pathogenic].
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FBN1. . Gene score misZ: 5.0644 (greater than the threshold 3.09). Trascript score misZ: 8.1787 (greater than threshold 3.09). The gene has 1311 curated pathogenic missense variants (we use a threshold of 10). The gene has 112 curated benign missense variants. GenCC has associacion of the gene with MASS syndrome, Weill-Marchesani syndrome, geleophysic dysplasia, Shprintzen-Goldberg syndrome, Acromicric dysplasia, familial thoracic aortic aneurysm and aortic dissection, progeroid and marfanoid aspect-lipodystrophy syndrome, ectopia lentis 1, isolated, autosomal dominant, Marfan syndrome, Weill-Marchesani syndrome 2, dominant, isolated ectopia lentis, neonatal Marfan syndrome, stiff skin syndrome.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.991
PP5
Variant 15-48494209-C-T is Pathogenic according to our data. Variant chr15-48494209-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 519733.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 29
GnomAD4 exome
Cov.:
29
GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 23, 2016 | The p.C908Y pathogenic mutation (also known as c.2723G>A), located in coding exon 22 of the FBN1 gene, results from a G to A substitution at nucleotide position 2723. The cysteine at codon 908 is replaced by tyrosine, an amino acid with highly dissimilar properties, and is located in the hybrid motif #02 domain. This alteration was shown to segregate with Marfan syndrome (MFS) in several members of a family. The proband, who was reported to also have MFS, did not carry this alteration, but the clinical diagnosis was described as debatable (Judge DP et al. Am J Med Genet. 2001;99:39-47). This alteration has also been reported in individuals with ectopia lentis or thoracic aortic aneurysm and dissection (Li D et al. Genet Test. 2008;12:325-30; Wang WJ et al. J Mol Med. 2013;91:37-47). Alterations at the same amino acid position, C905G and C908R, have also been detected in patients with MFS (Haine E et al. J Bone Miner Res. 2015;30:1369-76; Katzke S et al. Hum Mutat. 2002;20:197-208; Stheneur C et al. Eur J Hum Genet. 2009;17:1121-8). The majority of FBN1 mutations identified to date have involved the substitution or generation of cysteine residues within cbEGF domains (Vollbrandt T et al. J Biol Chem. 2004;279(31):32924-32931). And internal structural analysis indicates that p.C908Y eliminates a conserved disulfide motif in TB-hybrid domain 2 of fibrillin-1, which is expected to result in a more dynamic structure in this part of the protein (Jensen SA et al. Structure. 2009;17:759-68). Based on the available evidence, C908Y is classified as a pathogenic mutation. - |
Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 05, 2018 | Variant summary: FBN1 c.2723G>A (p.Cys908Tyr) results in a non-conservative amino acid change located to the second hybrid motif (Li 2008) in 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 246192 control chromosomes (gnomAD and publication data). The variant, c.2723G>A, has been reported in the literature in multiple individuals affected with Marfan Syndrome (Judge 2001, Li 2008). The variant was shown to segregate with the disease in these two families, with all the patients having somewhat atypical (i.e. mild to moderate) features. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Isolated thoracic aortic aneurysm Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | research | Department of Vascular Biology, Beijing Anzhen Hospital | Sep 01, 2018 | - - |
not provided Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2019 | - - |
FBN1-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 21, 2024 | The FBN1 c.2723G>A variant is predicted to result in the amino acid substitution p.Cys908Tyr. This variant has been reported in multiple unrelated individuals with Marfan syndrome or related phenotypes and found to segregate within families. Of note, intrafamilial phenotypic variability has been documented for this variant (Judge et al. 2001. PubMed ID: 11170092; Li et al. 2008. PubMed ID: 18471089; Table S3, Li et al. 2021. PubMed ID: 33824467). This variant has not been reported in a large population database, indicating this variant is rare. Different nucleotide substitutions affecting the same amino acid (p.Cys908Gly, p.Cys908Arg, p.Cys908Trp, and p.Cys908Ser) have been reported in individuals with Marfan syndrome or related phenotypes (Human Gene Mutation Database). Taken together, the c.2723G>A (p.Cys908Tyr) variant is interpreted as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Uncertain
D
Vest4
MutPred
Gain of phosphorylation at C908 (P = 0.0186);
MVP
MPC
ClinPred
D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at