ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.6354C>T (p.Ile2118=) (rs112989722)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000017912 SCV000058886 likely pathogenic Marfan syndrome 2011-06-24 criteria provided, single submitter clinical testing The Ile2118Ile variant has previously been reported in 4 individuals with clinic al features of Marfan syndrome (Liu 1997, Miller 2007, Attanasio 2008, Pilop 200 9) and was absent from 190 control chromosomes (Liu 1997). Although this variant does not lead to an amino acid change, functional studies have shown that this variant induces the skipping of exon 51 leading to the in-frame deletion of 22 a mino acids (Liu 1997). Therefore, this variant is likely to be pathogenic.
Ambry Genetics RCV000245874 SCV000319336 pathogenic Cardiovascular phenotype 2014-11-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Functionally-validated splicing mutation
GeneDx RCV000483725 SCV000564993 likely pathogenic not provided 2017-12-11 criteria provided, single submitter clinical testing The c.6354 C>T variant that is likely pathogenic was identified in the FBN1 gene. This variant has been reported previously in several individuals with confirmed or suspected diagnoses of Marfan syndrome (Miller et al., 2007; Attanasio et al., 2008; Pilop et al., 2009; Pees et al., 2014). This variant has also been identified in one other individual with a clinical diagnosis of Marfan syndrome tested at GeneDx, and it has been classified as pathogenic or likely pathogenic by other clinical laboratories (SCV000058886.4; SCV000319336.2; Landrum et al., 2016). Although this variant results in a synonymous amino acid change (I2118I), RT-PCR studies have demonstrated that c.6354 C>T results in skipping of exon 52 (reported as exon 51 due to alternative nomenclature) (Liu et al., 1997). Furthermore, RNA sequencing of aortic tissue from a patient harboring this variant revealed loss of all exon 52 nucleotides (reported as exon 51) (Miller et al., 2007). Other splicing variants have been reported in the FBN1 gene in association with Marfan syndrome (Stenson et al., 2014). Additionally, the c.6354 C>T variant was not observed at a significant frequency in large population cohorts (Lek et al., 2016).
Integrated Genetics/Laboratory Corporation of America RCV000589136 SCV000695579 pathogenic Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections 2017-06-07 criteria provided, single submitter clinical testing Variant summary: The FBN1 c.6354C>T (p.Ile2118Ile) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, this synonomous variant disrupts a splice enhancer, resulting in an in-frame deletion of exon 51. This exon skipping has been supported by multiple publications in both an in vivo and in vitro setting. Exon 51 encodes part of a conserved cysteine-rich domain, and its loss is likely to significantly impact fibrillin function since mutation of FBN1 cysteine residues are a known MFS disease mechanism. This variant is absent in 120704 control chromosomes, and has been reported in MFS patients in the literature. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000704427 SCV000833376 pathogenic Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2018-05-11 criteria provided, single submitter clinical testing This sequence change affects codon 2118 of the FBN1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the FBN1 protein. This variant is not present in population databases (rs112989722, ExAC no frequency). This variant has been reported in several unrelated individuals affected with Marfan syndrome (PMID: 9241263, 17224687, 18435798, 19720936, 24199744). This variant has been observed in an individual with aortic root dilation and a Ghent criteria score >7, findings that are highly specific for Marfan syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 16449). Experimental studies have shown that this silent change causes a splicing defect leading to the complete loss of exon 51 both in vivo and in vitro. (PMID: 9241263, 16995940, 17224687, 17884807, 19720936). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000017912 SCV000038191 pathogenic Marfan syndrome 1997-08-01 no assertion criteria provided literature only

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