Submissions for variant NM_000138.5(FBN1):c.6431A>G (p.Asn2144Ser)

dbSNP: rs137854461

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000524502	SCV000283644	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 2144 of the FBN1 protein (p.Asn2144Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Marfan syndrome (PMID: 8504310, 12938084, 16220557, 17657824). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Asn1246Ser. ClinVar contains an entry for this variant (Variation ID: 16431). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FBN1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects FBN1 function (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 National Research Centre 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170530	SCV001333114	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2018-06-27	criteria provided, single submitter	clinical testing
GeneDx	RCV001836710	SCV002097426	pathogenic	not provided	2022-02-08	criteria provided, single submitter	clinical testing	Observed de novo in a child with dental crowding and scoliosis enrolled in a whole exome sequencing study for intellectual disability and developmental delay, considered a secondary finding (Thompson et al., 2018); Not observed in large population cohorts (gnomAD); Functional studies suggest a damaging effect with reduced calcium-binding affinity and irregular microfibril assembly (Handford et al., 1995; Yuan et al., 2002; Shiga et al., 2008); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar (ClinVar Variant ID# 16431); This variant is associated with the following publications: (PMID: 11829507, 7896820, 18049824, 8504310, 16220557, 17657824, 19293843, 19533785, 27611364, 29790872, 12938084, 32679894, 9887276)
Institute of Human Genetics, University of Leipzig Medical Center	RCV000017893	SCV004100762	pathogenic	Marfan syndrome	2023-09-28	criteria provided, single submitter	clinical testing	Criteria applied: PS2_VSTR,PM5_STR,PS4_MOD,PM1,PM2_SUP,PP3,PP4
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV001836710	SCV005196670	pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
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