rs111984349
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP2PP3_StrongPP5
The NM_000138.5(FBN1):c.7828G>A(p.Glu2610Lys) variant causes a missense change involving the alteration of a conserved nucleotide. 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. E2610V) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000138.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FBN1 | NM_000138.5 | c.7828G>A | p.Glu2610Lys | missense_variant | 64/66 | ENST00000316623.10 | |
FBN1 | NM_001406716.1 | c.7828G>A | p.Glu2610Lys | missense_variant | 63/65 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBN1 | ENST00000316623.10 | c.7828G>A | p.Glu2610Lys | missense_variant | 64/66 | 1 | NM_000138.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Marfan syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Center for Human Genetics, Inc, Center for Human Genetics, Inc | Nov 01, 2016 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Center for Medical Genetics Ghent, University of Ghent | Nov 07, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | research | Centre of Medical Genetics, University of Antwerp | Mar 01, 2021 | PM2, PS6, PP4 - |
Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 16, 2022 | The p.E2610K pathogenic mutation (also known as c.7828G>A), located in coding exon 63 of the FBN1 gene, results from a G to A substitution at nucleotide position 7828. The glutamic acid at codon 2610 is replaced by lysine, an amino acid with similar properties, and is located in the cbEGF-like #42 domain. This mutation has been reported in several individuals with a diagnosis of Marfan syndrome based on Ghent criteria and has been reported as de novo in several cases (Liu WO et al. Genet. Test. 1997-1998;1(4):237-42; Arbustini E et al. Hum Mutat. 2005 Nov;26(5):494; Baetens M et al. Hum Mutat. 2011;32(9):1053-62; Baetens M et al. Hum Mutat, 2011 Sep;32:1053-62; Becerra-Muñoz VM et al. Orphanet J Rare Dis, 2018 01;13:16). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 08, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17657824, 35058154, 31098894, 33436942, 33824467, 10533071, 17701892, 16222657, 10464652, 29357934, 21542060, 27724990, 24161884, 26133393, 20591885) - |
Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 05, 2023 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 2610 of the FBN1 protein (p.Glu2610Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Marfan syndrome (PMID: 10464652, 10533071, 16222657, 17657824, 17701892, 21542060, 24161884). ClinVar contains an entry for this variant (Variation ID: 264272). 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 FBN1 protein function. For these reasons, this variant has been classified as Pathogenic. - |
Marfan syndrome;C0265287:Acromicric dysplasia;C1858556:MASS syndrome;C1861456:Stiff skin syndrome;C1869115:Weill-Marchesani syndrome 2, dominant;C3280054:Geleophysic dysplasia 2;C3541518:Ectopia lentis 1, isolated, autosomal dominant;C4310796:Progeroid and marfanoid aspect-lipodystrophy syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Isolated thoracic aortic aneurysm Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Department of Vascular Biology, Beijing Anzhen Hospital | Sep 01, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at