rs137854464
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_000138.5(FBN1):c.7339G>A(p.Glu2447Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,614,014 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. E2447Q) 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 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FBN1 | NM_000138.5 | c.7339G>A | p.Glu2447Lys | missense_variant | 60/66 | ENST00000316623.10 | |
FBN1 | NM_001406716.1 | c.7339G>A | p.Glu2447Lys | missense_variant | 59/65 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBN1 | ENST00000316623.10 | c.7339G>A | p.Glu2447Lys | missense_variant | 60/66 | 1 | NM_000138.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152198Hom.: 0 Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461816Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727220
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152198Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74352
ClinVar
Submissions by phenotype
Marfan syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 18, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Center of Genomic medicine, Geneva, University Hospital of Geneva | Nov 04, 2015 | - - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 22, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 10, 2022 | 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: 15054843, 8188302, 8136837, 17657824, 20564469, 26787436, 10229672, 11826022, 20591885) - |
Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 16, 2019 | The p.E2447K variant (also known as c.7339G>A), located in coding exon 59 of the FBN1 gene, results from a G to A substitution at nucleotide position 7339. The glutamic acid at codon 2447 is replaced by lysine, an amino acid with similar properties, and is located in the cbEGF-like #38 domain. This alteration has been detected in association with ectopia lentis (Kainulainen K et al. Nat. Genet. 1994;6:64-9 (reported as p.E1549K); Lönnqvist L et al. Genomics. 1994;19:573-6) and Marfan Syndrome (Comeglio P et al. Hum. Mutat. 2007;28:928; Franken R et al. Eur. Heart J. 2016;37:3285-3290). In one family, this variant segregated with ectopia lentis and/or skeletal abnormalities in five individuals, while absent in two unaffected family members (Lönnqvist L et al. Genomics. 1994;19:573-6). One functional study has suggested that this variant exposes a cryptic metalloproteinase cleavage site, but the physiological relevance of the result is unclear (Ashworth JL et al. Biochem. J. 1999;340(Pt 1):171-81). 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 majority of available evidence to date, this variant is likely to be pathogenic. - |
Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 19, 2023 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 2447 of the FBN1 protein (p.Glu2447Lys). 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 missense change has been observed in individuals with ectopia lentis or Marfan syndrome (PMID: 8136837, 8188302, 11826022, 17657824, 20564469, 26787436). It has also been observed to segregate with disease in related individuals. This variant is also known as Glu1549Lys. ClinVar contains an entry for this variant (Variation ID: 16437). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects FBN1 function (PMID: 10229672). For these reasons, this variant has been classified as Pathogenic. - |
Ectopia lentis 1, isolated, autosomal dominant Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 2007 | - - |
Connective tissue disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital | Jul 30, 2019 | patient has a personal and family history of Marfan, patient has additional connective tissue related disorder. Variant was identified in homozygous form. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at