rs111401431
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2PP2PP3_ModeratePP5_Very_Strong
The NM_000138.5(FBN1):c.4588C>T(p.Arg1530Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 11/18 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000138.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461832Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727222
GnomAD4 genome
ClinVar
Submissions by phenotype
Marfan syndrome Pathogenic:7
This variant is interpreted as a Likely Pathogenic, for Marfan syndrome, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PMID:19941982). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => PS4 downgraded in strength to Moderate. Observed in several unrelated affected individuals and absent from population databases (ExAC and gnomAD) (PMID:11700157) (PMID:17663468) (PMID:14695540) (PMID:17679947) (PMID:19941982). PP3-Moderate => PP3 upgraded in strength to Moderate. Mutation creates a cystein residue. The majority of FBN1 mutations involve substitution or creation of cystein residues. -
PM2, PS1, PP4 -
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This missense variant replaces arginine with cysteine at codon 1530 in a TGFbeta-like domain of the FBN1 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. Cysteine creating variants in cbEGF-like and TGFbeta-like domains have been shown to affect protein stability and are overrepresented among patients with Marfan syndrome (PMID: 15161917, 16571647, 17701892). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in more than 10 individuals affected with Marfan syndrome (PMID: 17663468, 19863550, 22772377, 24161884, 24793577, 25907466, 28941062, 29198452, 29357934, 30393980, 30838813, 31730815, 31825148) and in multiple individuals affected with ectopia lentis (PMID: 11700157, 14695540, 17679947, 19941982, 20564469, 24698609, 31098894, 36729443, 38190127). It has also been reported in multiple individuals suspected to be affected with Marfan syndrome (PMID: 17253931, 17627385, 25652356, 29768367, 31536524) and in one individual affected with thoracic aortic aneurysm (PMID: 28550590). It has been shown that this variant segregates with disease in multiple affected individuals across multiple families (PMID: 17663468, 17679947, 19941982, 29357934, 36729443). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
ACMG criteria used to clasify this variant: PP3, PS4, PM2, PM5, PP1, PP2 -
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not provided Pathogenic:6
PP1_moderate, PP3, PM1, PM2, PM6, PS4 -
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Identified in a patient with bilateral ectopia lentis (Cappuccio et al., 2022); this patient was also hemizygous for a variant in the RPL10 gene and had a history of severe intellectual disability, dysmorphic features, retinitis pigmentosa and cryptorchidism; 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: 24698609, 23794388, 20021881, 17679947, 17627385, 20564469, 16971892, 15054843, 19941982, 22772377, 27647783, 17663468, 14695540, 17253931, 11700157, 19863550, 29768367, 29198452, 30838813, 31098894, 29357934, 31536524, 31825148, 31730815, 34818515, 24161884, 35058154, 35876338) -
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The FBN1 c.4588C>T, p.Arg1530Cys variant (rs111401431) has been reported in multiple individuals with Marfan syndrome or Marfan-like symptoms such as ectopia lentis and aortic dissection (Aragon-Martin 2010, Biggin 2004, Howarth 2007, Jin 2007, Loeys 2001, Rand-Hendriksen 2007, Tjeldhorn 2006, Villamizar 2010, Wang 2013, Yoo 2010). It is listed as pathogenic in ClinVar (Variation ID: 36078), and not observed in the general population databases. The variant creates a novel cysteine residue in the FBN1 protein, which is considered causal for Marfan syndrome according to the revised Ghent nosology (Loeys 2010). Based on the above information, the p.Arg1530Cys variant is classified as pathogenic. References: Aragon-Martin J et al. Role of ADAMTSL4 mutations in FBN1 mutation-negative ectopia lentis patients. Hum Mutat. 2010; 31(8):E1622-31. Biggin A et al. Detection of thirty novel FBN1 mutations in patients with Marfan syndrome or a related fibrillinopathy. Hum Mutat. 2004; 23(1):99. Howarth R et al. Application of dHPLC for mutation detection of the fibrillin-1 gene for the diagnosis of Marfan syndrome in a National Health Service Laboratory. Genet Test. 2007; 11(2):146-52. Jin C et al. Novel FBN1 mutations associated with predominant ectopia lentis and marfanoid habitus in Chinese patients. Mol Vis. 2007; 13:1280-4. Loeys B et al. Genotype and phenotype analysis of 171 patients referred for molecular study of the fibrillin-1 gene FBN1 because of suspected Marfan syndrome. Arch Intern Med. 2001; 2001 Nov 12;161(20):2447-54. Loeys B et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet. 2010; 47(7):476-85. Rand-Hendriksen S et al. Search for correlations between FBN1 genotype and complete Ghent phenotype in 44 unrelated Norwegian patients with Marfan syndrome. Am J Med Genet A. 2007; 143A(17):1968-77. Tjeldhorn L et al. Rapid and efficient FBN1 mutation detection using automated sample preparation and direct sequencing as the primary strategy. Genet Test. 2006; 10(4):258-64. Villamizar C et al. Paucity of skeletal manifestations in Hispanic families with FBN1 mutations. Eur J Med Genet. 2010; 53(2):80-4. Wang W et al. Exon 47 skipping of fibrillin-1 leads preferentially to cardiovascular defects in patients with thoracic aortic aneurysms and dissections. J Mol Med (Berl). 2013; 91(1):37-47. Yoo E et al. Clinical and genetic analysis of Korean patients with Marfan syndrome: possible ethnic differences in clinical manifestation. Clin Genet. 2010; 77(2):177-82. -
Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
The p.R1530C pathogenic mutation (also known as c.4588C>T), located in coding exon 37 of the FBN1 gene, results from a C to T substitution at nucleotide position 4588. The arginine at codon 1530 is replaced by cysteine, an amino acid with highly dissimilar properties. 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). This pathogenic mutation has been identified in multiple individuals with ectopia lentis (EL); some of these individuals also met Ghent criteria while some did not (Loeys B et al. Arch Intern Med. 2001;161(20):2447-54; Biggin A et al. Hum Mutat. 2004;23(1):99; Jin C et al. Mol Vis. 2007;13:1280-4; Aragon-Martin JA et al. Hum Mutat. 2010;31(8):E1622-31; Vanem TT et al. Am J Med Genet A. 2020 02;182(2):397-408). This mutation was found to co-segregate with disease in two unrelated families (Rand-Hendriksen S et al. Am J Med Genet A. 2007;143A(17):1968-77; Mannucci L et al. Clin Chim Acta. 2020 Feb;501:154-164; Villamizar C et al. Eur J Med Genet. 2010; 53(2):80-4). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections Pathogenic:1
Variant summary: FBN1 c.4588C>T (p.Arg1530Cys) results in a non-conservative amino acid change 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 251128 control chromosomes. c.4588C>T has been reported in the literature in multiple individuals affected with Marfan Syndrome and the variant has been shown to segregate with disease (eg. Loeys_2001, Biggin_2004, Tjeldhorn_2006, Jin_2007, Howarth_2007, etc). These data indicate that the variant is very likely to be associated with disease. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
FBN1-related disorder Pathogenic:1
The FBN1 c.4588C>T variant is predicted to result in the amino acid substitution p.Arg1530Cys. This variant has been reported in multiple individuals with ectopia lentis, and in some cases was determined to have arisen de novo (see for examples Loeys et al. 2001. PubMed ID: 11700157; Khan et al. 2014. PubMed ID: 24698609; Li et al. 2019. PubMed ID: 31098894). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Given the evidence, we interpret c.4588C>T (p.Arg1530Cys) as pathogenic. -
Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1530 of the FBN1 protein (p.Arg1530Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Marfan syndrome (PMID: 11700157, 14695540, 17253931, 17627385, 17663468, 17679947, 19863550). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 36078). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt FBN1 protein function with a positive predictive value of 95%. 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
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at