ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.5519G>A (p.Arg1840His)

gnomAD frequency: 0.00003  dbSNP: rs369482365
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000757277 SCV000885436 uncertain significance not specified 2019-02-19 criteria provided, single submitter clinical testing The FBN1 c.5519G>A, p.Arg1840His variant (rs369482365) has not been reported in the medical literature, listed in gene-specific variant databases, or reported in the ClinVar database. However, ARUP Laboratories has previously detected this variant in an individual with a dilated aortic root and suspected connective tissue disorder. It is observed once in the Exome Variant Server population database (1/12988 alleles). The arginine at position 1840 is moderately conserved and computational algorithms (PolyPhen-2, SIFT) predict that the variant is deleterious. This variant occurs in a conserved EGF domain but does not occur in a conserved residue, which is a known pathogenic mechanism (Loeys 2010). Due to the limited information regarding the p.Arg1840His variant, its clinical significance could not be determined with certainty. References: Loeys BL et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet. 2010 Jul;47(7):476-85.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV001258186 SCV001435075 uncertain significance Marfan syndrome criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001342803 SCV001536750 uncertain significance Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2021-08-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 1840 of the FBN1 protein (p.Arg1840His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with aortic dissection (Invitae). ClinVar contains an entry for this variant (Variation ID: 618652). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics RCV002485965 SCV002780890 uncertain significance Ectopia lentis 1, isolated, autosomal dominant; Marfan syndrome; MASS syndrome; Stiff skin syndrome; Weill-Marchesani syndrome 2, dominant; Acromicric dysplasia; Geleophysic dysplasia 2; Progeroid and marfanoid aspect-lipodystrophy syndrome 2021-11-12 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV001258186 SCV004822541 uncertain significance Marfan syndrome 2023-11-14 criteria provided, single submitter clinical testing

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