Submissions for variant NM_000138.5(FBN1):c.1030C>T (p.Arg344Cys)

gnomAD frequency: 0.00001  dbSNP: rs752010116

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen FBN1 Variant Curation Expert Panel, ClinGen	RCV000663437	SCV004123034	likely pathogenic	Marfan syndrome	2023-11-16	reviewed by expert panel	curation	NM_00138 c.1030C>T is a missense variant in FBN1 predicted to cause a substitution of an arginine by cysteine at amino acid 344 (p.Arg344Cys). This variant was found in one published proband with unspecified ocular and skeletal features, one internal proband with ectopia lentis and a systemic score of 3, and two probands with isolated thoracic aortic aneurysm and dissection, none of whom met the revised Ghent criteria for Marfan syndrome (PS4_moderate; PMID: 25652356; UZG & Invitae internal data, ClinVar Variation ID: 548999). This variant is present in gnomAD v2.1.1 (3/113642 [0.0026%] European alleles; https://gnomad.broadinstitute.org/). This variant introduces a novel cysteine residue which may impede the normal formation of critical disulfide bridges (PM1). Computational prediction tools and conservation analysis suggest that this variant may impact protein structure or function (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: PS4_moderate, PM1, PP2, PP3.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170324	SCV001332894	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2018-06-04	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001170324	SCV001344994	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2020-03-23	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 344 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 3/251326 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.
Invitae	RCV001855410	SCV002230465	uncertain significance	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2022-04-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 344 of the FBN1 protein (p.Arg344Cys). This variant is present in population databases (rs752010116, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of FBN1-related conditions (PMID: 25652356; Invitae). ClinVar contains an entry for this variant (Variation ID: 548999). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
GeneDx	RCV002245070	SCV002513019	likely pathogenic	not provided	2021-11-02	criteria provided, single submitter	clinical testing	Identified in a patient with suspected Marfan syndrome in published literature (Baudhuin LM et al., 2015); Introduces a new cysteine residue within a TGF-binding protein domain (aka TB domain or 8-Cysteine domain) and is expected to disrupt disulfide bonding within this domain; other missense substitutions that affect cysteine residues within this TGF-binding protein domain have been reported in association with various FBN1-related phenotypes, including Marfan syndrome (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25652356)
Ambry Genetics	RCV001170324	SCV002696325	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2017-04-04	criteria provided, single submitter	clinical testing	The p.R344C variant (also known as c.1030C>T), located in coding exon 9 of the FBN1 gene, results from a C to T substitution at nucleotide position 1030. The arginine at codon 344 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in the TGFBP #1 domain. This alteration was detected in an individual who exhibited Marfan syndrome-like skeletal and ocular features (Baudhuin LM et al. J. Hum. Genet., 2015 May;60:241-52). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Center for Medical Genetics Ghent, University of Ghent	RCV000663437	SCV000786727	uncertain significance	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing