ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.4588C>T (p.Arg1530Cys) (rs111401431)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000029740 SCV000052393 pathogenic Marfan syndrome 2011-08-18 criteria provided, single submitter curation Converted during submission to Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000029740 SCV000058849 pathogenic Marfan syndrome 2008-01-17 criteria provided, single submitter clinical testing
Ambry Genetics RCV000254448 SCV000319850 pathogenic Cardiovascular phenotype 2015-07-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Good segregation with disease (lod 1.5-3 = 5-9 meioses),Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000724901 SCV000332283 pathogenic not provided 2015-06-19 criteria provided, single submitter clinical testing
Invitae RCV000524499 SCV000544939 pathogenic Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2018-11-06 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 1530 of the FBN1 protein (p.Arg1530Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (rs111401431, ExAC no frequency). This variant has been reported in several individuals affected with Marfan syndrome (PMID: 14695540, 17253931, 17627385, 17663468, 19863550) or ectopia lentis (PMID: 11700157, 17679947). It has also been shown to segregate with Marfan syndrome in a small family (PMID: 19941982). This variant affects a cysteine residue located within a TGFBP domain of the FBN1 protein. Cysteine residues in these domains are believed to be involved in intramolecular disulfide bridges and to be important for FBN1 structure. Although the exact function of the FBN1 TGFBP domains has not being elucidated (PMID: 10930463, 27437668), missense substitutions within the TGFBP domains affecting cysteine residues are significantly overrepresented among patients with Marfan syndrome (PMID: 16571647, 17701892). In summary, this variant has been found in multiple individuals with FBN1-related diseases, is not present in population databases, and likely has a deleterious effect on the protein function. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000515364 SCV000611191 pathogenic Ectopia lentis, isolated, autosomal dominant; Marfan syndrome; MASS syndrome; Stiff skin syndrome; Weill-Marchesani syndrome 2; Acromicric dysplasia; Geleophysic dysplasia 2; Marfan lipodystrophy syndrome 2017-05-18 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000029740 SCV000740504 pathogenic Marfan syndrome 2017-06-14 criteria provided, single submitter clinical testing
SIB Swiss Institute of Bioinformatics RCV000029740 SCV000803472 likely pathogenic Marfan syndrome 2018-05-31 criteria provided, single submitter curation 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.
Center for Medical Genetics Ghent,University of Ghent RCV000029740 SCV000787081 likely pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing

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