ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.2242T>C (p.Cys748Arg) (rs397515765)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000035134 SCV000058775 likely pathogenic Marfan syndrome 2010-11-03 criteria provided, single submitter clinical testing The 2242T>C (Cys748Arg) variant has not been previously reported in the literatu re or been previously identified by our laboratory. A different variant at the s ame amino acid position (Cys748Tyr) has been reported in the literature in two a ffected individuals and was observed to segregate with disease in one family (Ka tzke 2002, Halliday 2002). Cystine at position 748 of FBN1 is highly conserved a cross several evolutionarily distant species, increasing the likelihood that thi s change is pathogenic. In addition, this variant affects a cysteine residue and cysteine substitutions are a common finding in individuals with Marfan syndrome (Schrijver 1999). Therefore, this variant is likely to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000587001 SCV000695483 likely pathogenic Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections 2017-05-05 criteria provided, single submitter clinical testing Variant summary: The FBN1 c.2242T>C (p.Cys748Arg) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant lies in a conserved region within EGF-like #07. "The sulfhydryl group of cysteine is unique in its ability to participate in disulfide covalent cross-linkage . In fact, two thirds of fibrillin cysteine residues exist in the half-cystinyl form, suggesting their participation in intramolecular disulfide linkage. The cysteine residues in the EGF-like motif may also be necessary for intermolecular interactions with other fibrillin molecules or with other proteins (Dietz_1992)." Therefore, alteration of cysteine in this domain could disrupt disulfide binding, effecting secondary or tertiary structure or possibly impairing fibrillin interactions. This variant is absent in 121350 control chromosomes and has been reported in a patient with MFS in the literature. A different variant involving the same codon (p.Cys748Tyr) has been reported in MFS patients in the literature (Halliday_2002, Katzke_2002), which supports the functional role of this amino acid position. In addition, one clinical diagnostic laboratory has classified this variant as likely pathogenic. Taken together, this variant is classified as "likely pathogenic,"until additional evidence becomes available.
Institute of Human Genetics,University Medical Center Hamburg-Eppendorf RCV000035134 SCV000897658 likely pathogenic Marfan syndrome 2018-11-20 criteria provided, single submitter clinical testing

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