rs137854476
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000138.5(FBN1):c.1585C>T(p.Arg529*) variant causes a stop gained change involving the alteration of a non-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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000138.5 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 32
GnomAD4 genome
ClinVar
Submissions by phenotype
Marfan syndrome Pathogenic:4
PM2, PVS1, PP1-M, PP4 -
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Familial thoracic aortic aneurysm and aortic dissection Pathogenic:2
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The p.R529* pathogenic mutation (also known as c.1585C>T), located in coding exon 12 of the FBN1 gene, results from a C to T substitution at nucleotide position 1585. This changes the amino acid from an arginine to a stop codon within coding exon 12. This alteration has been reported in several individuals with a clinical or suspected diagnosis of Marfan syndrome (Montgomery RA et al. Am. J. Hum. Genet., 1998 Dec;63:1703-11; Rand-Hendriksen S et al. Am J Med Genet A, 2007 Sep;143A:1968-77; Ma M et al. Mol Med Rep, 2016 Jul;14:151-8;Mannucci L et al. Clin Chim Acta, 2020 Feb;501:154-164). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
not specified Pathogenic:1
The FBN1 c.1585C>T; p.Arg529Ter variant (rs137854476) has been reported multiple times in the literature in individuals with Marfan syndrome (Hung 2009, Montgomery 1998, Rand-Hendriksen 2007, Soylen 2009, Stheneur 2009, Tjeldhorn 2006). It is reported as pathogenic in the ClinVar database (Variation ID: 16452), and is absent from general population databases (1000 Genome Project, Exome Variant Server, Genome Aggregation Database). This variant induces an early termination codon and is predicted to result in a truncated protein or absent transcript. Taken together, this variant is considered pathogenic. REFERENCES Link to ClinVar database for p.Arg529Ter: https://www.ncbi.nlm.nih.gov/clinvar/variation/16452/ Hung CC et al. Mutation spectrum of the fibrillin-1 (FBN1) gene in Taiwanese patients with Marfan syndrome. Ann Hum Genet. 2009 Nov;73(Pt 6):559-67. Montgomery RA et al. Multiple molecular mechanisms underlying subdiagnostic variants of Marfan syndrome. Am J Hum Genet. 1998 Dec;63(6):1703-11. 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 Sep 1;143A(17):1968-77. Soylen B et al. Prevalence of dural ectasia in 63 gene-mutation-positive patients with features of Marfan syndrome type 1 and Loeys-Dietz syndrome and report of 22 novel FBN1 mutations. Clin Genet. 2009 Mar;75(3):265-70. Stheneur C et al. Identification of the minimal combination of clinical features in probands for efficient mutation detection in the FBN1 gene. Eur J Hum Genet. 2009 Sep;17(9):1121-8. Tjeldhorn L et al. Rapid and efficient FBN1 mutation detection using automated sample preparation and direct sequencing as the primary strategy. Genet Test. 2006 Winter;10(4):258-64. -
Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections Pathogenic:1
Variant summary: The FBN1 c.1585C>T (p.Arg529X) variant causes a nonsense mutation resulting in a premature termination codon, which is a commonly known mechanisms for disease. The variant of interest was not observed in controls (ExAC, 1000 Gs or ESP) and has been reported in multiple affected individuals via publications, In addition, a reputable database and clinical laboratory have cited the variant as "pathogenic." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Pathogenic. -
not provided Pathogenic:1
Not observed in large population cohorts (gnomAD); Published functional study demonstrates near absence of immunohistochemical staining of fibrillin-1 in cultured fibroblasts associated with the R529X variant (Montgomery et al., 1998); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 31098894, 19159394, 31730815, 27582083, 27175573, 9837823, 27611364, 21907952, 19839986, 19293843, 17663468, 31825148, 32854191, 34498425, 35058154, 30087447) -
Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 16452). This premature translational stop signal has been observed in individuals with Marfan syndrome (PMID: 9837823, 17663468, 27175573). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg529*) in the FBN1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FBN1 are known to be pathogenic (PMID: 17657824, 19293843). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at