Submissions for variant NM_000138.5(FBN1):c.4214T>G (p.Leu1405Arg)

gnomAD frequency: 0.00011  dbSNP: rs767606368

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen FBN1 Variant Curation Expert Panel, ClinGen	RCV000663701	SCV003762202	uncertain significance	Marfan syndrome	2022-12-01	reviewed by expert panel	curation	NM00138 c.4214T>G is a missense variant in FBN1 predicted to cause a substitution of leucine by an arginine at amino acid position 1405. This variant has been reported 14 times in ClinVar: 7 times as likely benign and 7 times as of uncertain significance (Variation ID: 200041). This variant has been reported in the literature and identified by multiple institutions in probands with various features of connective tissue but none with a diagnosis of Marfan syndrome (PMID: 19012347; Mayo Clinic, Bichat Hospital, Universitair Ziekenhuis Gent, Universitair Ziekenhuis Antwerpen). In one family, this variant was found to segregate with mitral valve dystrophy in one family member (Bichat Hospital). This variant has been identified in 0.021% (27/129150) of alleles in the European population in gnomAD v2.1.1 (BS1; https://gnomad.broadinstitute.org/variant/15-48764870-A-C). Computational prediction and evolutionary conservation anaylsis tools are unclear about this variant predicted impact (REVEL = 0.726 which is below 0.750 threshold). Due to there being insufficient evidence, this variant is classified as uncertain significance for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: BS1.
GeneDx	RCV000757265	SCV000233816	uncertain significance	not provided	2023-05-24	criteria provided, single submitter	clinical testing	Although located in a calcium-binding EGF-like domain of the FBN1 gene, it does not affect a cysteine residue within this domain; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN1 related disorders (Collod-Beroud et al., 2003); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24941995, 19012347, 26333736, 24833718, 25519456, 32938213, 12938084)
Invitae	RCV000471621	SCV000544946	likely benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-10-24	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000757265	SCV000885420	likely benign	not provided	2017-06-27	criteria provided, single submitter	clinical testing	The FBN1 c.4214T>G, p.Leu1405Arg variant was previously detected in a healthy adult tested at ARUP. It has been reported three times in the medical literature: in association with a connective tissue disorder with vascular involvement (Rybczynski et al., 2008), in association with adolescent idiopathic scoliosis (Buchan et al., 2014), and as a de novo variant in a patient with spontaneous coronary artery dissection (von Hundelshausen et al., 2015). However, this variant is found in the genome Aggregation Database with a general population frequency of 0.01% (30 out of 277,184 chromosomes), while ClinVar lists it as a variant of uncertain significance (ClinVar ID 200041). The majority of pathogenic missense mutations associated with Marfan syndrome involve alterations to conserved residues in critical EFG-like domains, and although this variant is located in one of these domains, it is not within the EGF consensus sequence defined in the Ghent criteria (Loeys 2010). Computational algorithms make conflicting predictions as to its effect on protein structure and function (SIFT: tolerated, Poly-Phen 2: benign, Mutation Taster: disease causing). Based on all available evidence, the c.4214T>G variant is likely to be benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000505775	SCV000919336	likely benign	not specified	2021-02-01	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.4214T>G (p.Leu1405Arg) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 251436 control chromosomes, predominantly at a frequency of 0.00021 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in FBN1 causing Aortopathy phenotype (0.00011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.4214T>G has been reported in the literature in a small family with Adoloscent idiopathic scoliosis in two siblings, but no significant features of Marfan syndrome, where it demonstrated incomplete segregation (unaffected mother with the variant) with disease (Buchan_2014, Haller_2015), a patient diagnosed with other connective tissue diseases with vascular involvement, but not Marfan syndrome (Rybczynski_2008), as a reportedly de-novo variant in a patient presenting with recurrent coronary dissections who did not fulfill the Ghent nosology for Marfan syndrome (von Hundelshausen_2015), in a family member of a kindred where the molecular basis of disease was attributed to a different cause, namely, a pathogenic variant in the COL5A1 gene (Richer_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Marfan syndrome and/or an FBN1 associated Aortopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=2; VUS, n=5). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign.
Illumina Laboratory Services, Illumina	RCV001116399	SCV001274467	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001116400	SCV001274468	likely benign	Weill-Marchesani syndrome	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV001116401	SCV001274469	likely benign	Geleophysic dysplasia	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV001116402	SCV001274470	likely benign	Acromicric dysplasia	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000663701	SCV001274471	uncertain significance	Marfan syndrome	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001116403	SCV001274472	likely benign	Ectopia lentis 1, isolated, autosomal dominant	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV001116404	SCV001274473	likely benign	Stiff skin syndrome	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Color Diagnostics, LLC DBA Color Health	RCV001116399	SCV001344541	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-02-23	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with arginine at codon 1405 of the FBN1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with a connective tissue disease with vascular involvement (PMID: 19012347), recurrent spontaneous coronary dissections (PMID: 25519456), adolescent idiopathic scoliosis (PMID: 26333736), or arterial aneurysm and dissection (PMID: 32938213). This variant has been identified in 31/282836 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001116399	SCV002041981	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2019-10-09	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001116399	SCV002627408	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-05-13	criteria provided, single submitter	clinical testing	The p.L1405R variant (also known as c.4214T>G), located in coding exon 34 of the FBN1 gene, results from a T to G substitution at nucleotide position 4214. The leucine at codon 1405 is replaced by arginine, an amino acid with dissimilar properties. This alteration was reported in individuals with connective tissue disease (Rybczynski M et al. Am. J. Med. Genet. A, 2008 Dec;146A:3157-66) and adolescent idiopathic scoliosis (Haller G et al. J Bone Joint Surg Am, 2015 Sep;97:1411-7). This alteration was also describe to occur de novo in a case of spontaneous coronary artery dissection (von Hundelshausen P et al. Thromb. Haemost., 2015 Mar;113:668-70). None of the individuals met the diagnosis criteria for Marfan syndrome. In addition, one group also reported to detect this alteration in the in-house exome cases, including children without known vascular manifestations (von Hundelshausen P et al. Thromb. Haemost., 2015 Mar;113:668-70). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV003407671	SCV004113234	uncertain significance	FBN1-related condition	2023-09-23	criteria provided, single submitter	clinical testing	The FBN1 c.4214T>G variant is predicted to result in the amino acid substitution p.Leu1405Arg. This variant has been reported in a patient with connective tissue disease and vascular involvement (Rybczynski et al. 2008. PubMed ID: 19012347). It has also been reported as a variant of uncertain significance in a patient with idiopathic scoliosis who did not have a dilated aorta or a clinical diagnosis of Marfan syndrome (Haller et al. 2015. PubMed ID: 26333736) and as a presumed pathogenic, de novo variant in a patient with recurrent spontaneous coronary dissection without Marfan syndrome (von Hundelshausen et al. 2014. PubMed ID: 25519456). This variant has conflicting interpretations regarding it pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/200041/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Center for Medical Genetics Ghent, University of Ghent	RCV000663701	SCV000787034	uncertain significance	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing