Submissions for variant NM_000138.5(FBN1):c.7003C>T (p.Arg2335Trp)

dbSNP: rs794728262

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen FBN1 Variant Curation Expert Panel, ClinGen	RCV000663920	SCV003762201	likely pathogenic	Marfan syndrome	2022-12-01	reviewed by expert panel	curation	NM_00138 c.7003C>T is a missense variant in FBN1 predicted to cause a substitution of an Arginine by Tryptophan at amino acid 2335 (p.Arg2335Trp). This variant was found in a proband with isolated thoracic aortic aneurysm and dissection and segregates with disease in at least 5 affected family members (PP1_strong). It has been reported 2 times in the literature in individuals with ectopia lentis but who did not meet revised Ghent criteria for Marfan syndrome (PMID: 29357934; PMID: 12203992) (PS4_moderate). This variant is not present in gnomAD v2.1.1 (PM2_supporting; https://gnomad.broadinstitute.org/). Computational prediction tools and conservation analysis suggest that this variant may impact the protein structure (REVEL: 0.841) (PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PP1_strong, PS4_moderate, PM2_supporting, PP2, PP3.
Invitae	RCV000695545	SCV000824052	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-03-12	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 200100). This missense change has been observed in individuals with clinical features of Marfan syndrome (PMID: 12203992, 29357934; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 2335 of the FBN1 protein (p.Arg2335Trp).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781372	SCV000919351	uncertain significance	not specified	2018-09-04	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.7003C>T (p.Arg2335Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 245130 control chromosomes. c.7003C>T has been reported in the literature in individuals affected with Marfan Syndrome. In one family, the variant was identified in a homozygous patient of unaffected consanguineous parents, both of whom were heterozygous. The younger brother of the proband also developed symptoms of MFS, though his genotype was not reported (Voermans_2009). These data indicate that the variant may be a mild mutation associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine	RCV000663920	SCV001426401	likely pathogenic	Marfan syndrome		criteria provided, single submitter	research
Color Diagnostics, LLC DBA Color Health	RCV003528148	SCV004357328	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2023-04-17	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 2335 in the TGFbeta-like domain of the FBN1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in homozygous state in at least two unrelated individuals affected with Marfan syndrome (PMID: 20135580, 35008861, 36449672), and in heterozygous state in two unrelated individuals affected with thoracic aortic aneurysm and aortic dissection (PMID: 36517271, ClinVar SCV003762201.2) and in two individuals suspected of having Marfan syndrome (PMID: 12203992, 29357934). It has been reported that this variant segregates with disease in one of the families (ClinVar SCV003762201.2). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
All of Us Research Program, National Institutes of Health	RCV000663920	SCV004830775	likely pathogenic	Marfan syndrome	2023-06-26	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 2335 in the TGFbeta-like domain of the FBN1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in homozygous state in at least two unrelated individuals affected with Marfan syndrome (PMID: 20135580, 35008861, 36449672), and in heterozygous state in two unrelated individuals affected with thoracic aortic aneurysm and aortic dissection (PMID: 36517271, ClinVar SCV003762201.2) and in two individuals suspected of having Marfan syndrome (PMID: 12203992, 29357934). It has been reported that this variant segregates with disease in one of the families (ClinVar SCV003762201.2). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Center for Medical Genetics Ghent, University of Ghent	RCV000663920	SCV000787289	uncertain significance	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing