ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.6431A>G (p.Asn2144Ser) (rs137854461)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000524502 SCV000283644 pathogenic Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2018-07-16 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 2144 of the FBN1 protein (p.Asn2144Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is not present in population databases (rs137854461, ExAC no frequency). This variant has been reported to segregate with Marfan syndrome in a family (PMID: 8504310). This variant is also known as p.Asn1246Ser in the literature. In addition, this variant has been reported in several unrelated individuals with Marfan syndrome  (PMID: 16220557, 17657824) and in affected individuals reported by the FBN1-UMD database (PMID: 12938084). ClinVar contains an entry for this variant (Variation ID: 16431). Experimental studies have shown that this missense change impairs the calcium binding properties of FBN1 (PMID: 7896820, 11829507). For these reasons, this variant has been classified as Pathogenic.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000017893 SCV000584088 pathogenic Marfan syndrome 2016-04-14 criteria provided, single submitter research
Petrovsky Russian Research Center of Surgery, The Federal Agency for Scientific Organizations RCV000017893 SCV000930630 pathogenic Marfan syndrome 2019-08-01 criteria provided, single submitter clinical testing The p.N2144S variant has been reported in various individuals (PMID: 17657824, 16220557) but is absent from large population studies. Clinvar has an entry for this variant (Variation ID:16431). Functional studies suggest change in EGF-like region weakening of the calcium-binding (PMID:8504310, 7896820, 11829507). Computational resources like Provean, SIFT, PolyPhen2 show damaging effect.
OMIM RCV000017893 SCV000038172 pathogenic Marfan syndrome 1993-04-01 no assertion criteria provided literature only
Center for Medical Genetics Ghent,University of Ghent RCV000017893 SCV000787231 likely pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing

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