Submissions for variant NM_000138.5(FBN1):c.7400A>G (p.Gln2467Arg)

gnomAD frequency: 0.00002  dbSNP: rs770839761

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000560403	SCV000627986	benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-07-16	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000995330	SCV001149442	likely benign	not provided	2022-06-01	criteria provided, single submitter	clinical testing	FBN1: PM1, BS2
Color Diagnostics, LLC DBA Color Health	RCV001177890	SCV001342189	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-05-01	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with arginine at codon 2467 of the FBN1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual suspected of having heritable thoracic aortic disorder (PMID: 29907982). This variant has been identified in 6/282758 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.
GeneDx	RCV000995330	SCV001990615	uncertain significance	not provided	2020-11-24	criteria provided, single submitter	clinical testing	Identified in a patient with aortic root aneurysm, dilated cardiomyopathy (DCM), and atrial fibrillation in the published literature (Overwater et al., 2018); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Reported in ClinVar but additional evidence is not available (ClinVar Variant ID#457260; Landrum et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; 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); This variant is associated with the following publications: (PMID: 29907982)
Ambry Genetics	RCV001177890	SCV002671231	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2018-01-19	criteria provided, single submitter	clinical testing	The p.Q2467R variant (also known as c.7400A>G), located in coding exon 59 of the FBN1 gene, results from an A to G substitution at nucleotide position 7400. The glutamine at codon 2467 is replaced by arginine, an amino acid with highly similar properties, and is located in the cbEGF-like #38 domain. An alternate substitution, p.Q2467P, has been reported in a Marfan syndrome cohort; however, clinical details were limited (Franken R et al. Eur. Heart J., 2016 Nov;37:3285-3290). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002506299	SCV002815017	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	2021-07-29	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004003795	SCV004816770	uncertain significance	Marfan syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with arginine at codon 2467 of the FBN1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual suspected of having heritable thoracic aortic disorder (PMID: 29907982). This variant has been identified in 6/282758 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.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000995330	SCV002035188	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000995330	SCV002037219	uncertain significance	not provided		no assertion criteria provided	clinical testing