Submissions for variant NM_000138.5(FBN1):c.4282C>T (p.Arg1428Cys)

gnomAD frequency: 0.00001  dbSNP: rs1258352189

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000817203	SCV000957752	uncertain significance	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2022-09-03	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Arg1428 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 29357934), which suggests that this may be a clinically significant amino acid residue. 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: 660076). This missense change has been observed in individual(s) with Marfan syndrome (PMID: 27112580). This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1428 of the FBN1 protein (p.Arg1428Cys).
Color Diagnostics, LLC DBA Color Health	RCV001525412	SCV001735502	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-03-15	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 1428 in EGF-like calcium-binding domain motif 24 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). Cysteine creating variants in cbEGF-like domains have been shown to affect protein stability and are overrepresented among patients with Marfan syndrome (PMID: 15161917, 16571647, 17701892). This variant has been reported in an individual affected with Marfan syndrome (PMID: 27112580). This variant has been identified in 3/251412 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg1428Pro, has also been reported in an individual affected with Marfan syndrome (PMID: 29357934), suggesting that arginine at this position is important for FBN1 protein function. Although there is a suspicion for a pathogenic role, the available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance
Fulgent Genetics, Fulgent Genetics	RCV002501125	SCV002794057	uncertain significance	Ectopia lentis 1, isolated, autosomal dominant; Marfan syndrome; MASS syndrome; Stiff skin syndrome; Weill-Marchesani syndrome 2, dominant; Acromicric dysplasia; Geleophysic dysplasia 2; Progeroid and marfanoid aspect-lipodystrophy syndrome	2021-09-10	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004001801	SCV004814744	uncertain significance	Marfan syndrome	2023-04-03	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 1428 in EGF-like calcium-binding domain motif 24 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). Cysteine creating variants in cbEGF-like domains have been shown to affect protein stability and are overrepresented among patients with Marfan syndrome (PMID: 15161917, 16571647, 17701892). This variant has been reported in an individual affected with Marfan syndrome (PMID: 27112580). This variant has been identified in 3/251412 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg1428Pro, has also been reported in an individual affected with Marfan syndrome (PMID: 29357934), suggesting that arginine at this position is important for FBN1 protein function. Although there is a suspicion for a pathogenic role, the available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance