rs113871094
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000138.5(FBN1):c.4786C>T(p.Arg1596*) 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.: 31
GnomAD4 genome
ClinVar
Submissions by phenotype
not provided Pathogenic:6
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PP1_strong, PP2, PM2, PS2_moderate, PS4_moderate, PVS1 -
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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; Not observed at significant frequency in large population cohorts (gnomAD); Identified in multiple unrelated individuals with a reported diagnosis of Marfan syndrome, or clinical manifestations of Marfan syndrome, referred for testing at GeneDx and in the published literature (Loeys et al., 2001; Maygar et al., 2009; Stheneur et al., 2009; Ogawa et al., 2011; Han et al., 2017; Zastrow et al., 2017 ); This variant is associated with the following publications: (PMID: 25525159, 21907952, 12938084, 19293843, 19618372, 28901506, 11700157, 17718856, 16756980, 15241795, 11933199, 35058154, 33282382, 31167969, 33461977, 36588568, 29768367, 28050602) -
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Marfan syndrome Pathogenic:4
This variant has been previously reported (PMID: 11700157) and was seen once in our laboratory de novo in a 3-year-old female with dysmorphisms, developmental delay, autism, hypotonia, relative macrocephaly, failure to thrive, congenital diaphragmatic hernia, recurrent umbilical hernia, pectus carinatum, joint laxity. She also carried a de novo nonsense variant in TRPS1. -
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The Arg1596X variant has been reported in 4 individuals with clinical features o f Marfan syndrome and was shown to segregate with clinical feature in one report ed family (Loeys 2001, De Backer 2007, Magyar 2009,). In addition, this variant has been identified in one individual with clinical features of Marfan syndrome by our laboratory. This nonsense variant leads to a premature termination codon at position 1596, which is predicted to lead to a truncated or absent protein. H eterozygous loss of function of the FBN1 gene is an established disease mechanis m in Marfan syndrome. In summary, this variant meets our criteria to be classifi ed as pathogenic (http://pcpgm.partners.org/LMM). -
PM2, PVS1, PP4 -
Familial thoracic aortic aneurysm and aortic dissection Pathogenic:2
The p.R1596* pathogenic mutation (also known as c.4786C>T), located in coding exon 38 of the FBN1 gene, results from a C to T substitution at nucleotide position 4786. This changes the amino acid from an arginine to a stop codon within coding exon 38. This variant has been detected in multiple individuals reported to have Marfan syndrome (MFS) or features consistent with MFS, and individuals from MFS cohorts (Loeys B et al. Arch Intern Med, 2001 Nov;161:2447-54; Spits C et al. Fertil Steril, 2006 Aug;86:310-20; De Backer J et al. Clin Genet, 2007 Sep;72:188-98; Magyar I et al. Hum Mutat, 2009 Sep;30:1355-64; Stheneur C et al. Eur J Hum Genet, 2009 Sep;17:1121-8Ogawa N et al. Am J Cardiol, 2011 Dec;108:1801-7; Han Q et al. Mol Med Rep, 2017 Nov;16:6620-6625; Hansen J et al. JCI Insight, 2019 Jun 4; Erhart P et al. J Thorac Dis, 2020 Nov;12:6806-6812). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -
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Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections Pathogenic:1
Variant summary: FBN1 c.4786C>T (p.Arg1596X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251144 control chromosomes. c.4786C>T has been reported in the literature in multiple individuals affected with Marfan Syndrome and has been shown to segregate with disease within families (e.g., Loeys_2001, Loeys_2004, Spits_2006, Magyar_2009, DeBacker_2007). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 11700157, 15241795, 16756980, 17718856, 19618372). ClinVar contains an entry for this variant (Variation ID: 36082). Based on the evidence outlined above, the variant was classified as pathogenic. -
Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
This sequence change creates a premature translational stop signal (p.Arg1596*) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Marfan syndrome (PMID: 11700157, 12938084, 17718856, 19618372, 21907952, 28050602). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 36082). 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