Submissions for variant NM_000138.5(FBN1):c.7379A>G (p.Lys2460Arg)

gnomAD frequency: 0.00008  dbSNP: rs144189837

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000995332	SCV000233903	uncertain significance	not provided	2023-03-07	criteria provided, single submitter	clinical testing	Has been reported in association with Marfan syndrome in published literature, and frequently referred to as a variant of uncertain significance (Howarth et al., 2007; Robinson et al., 2012; Yang et al., 2014; Campens et al., 2015; Overwater, et al., 2018).; Reported in cis with FBN1 p.(N542S) in a patient with bicuspid aortic valve, TAAD, and additional connective tissue features who also harbored variants in TGFBR3, NOTCH1, and LTBP1; the FBN1 variants segregated with systemic connective tissue features in his mother, and the TGFBR3 variant segregated with aortic root dilation in his father and siblings (Sticchi et al., 2018); At the protein level, in silico analysis supports that this missense variant does not alter protein structure/function; At the mRNA level, in silico analysis supports a deleterious effect on splicing; 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: 24055113, 25812041, 25637381, 24941995, 32123317, 25644172, 21895641, 29907982, 17627385, 30255099)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000181600	SCV000539152	uncertain significance	not specified	2016-07-26	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 1 Marfan proband, 4/5 papers in HGMD classify as VUS due to presence in ESP. ClinVar: 2 VUS
Ambry Genetics	RCV001190175	SCV000738747	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-05-26	criteria provided, single submitter	clinical testing	The p.K2460R variant (also known as c.7379A>G), located in coding exon 59 of the FBN1 gene, results from an A to G substitution at nucleotide position 7379. The lysine at codon 2460 is replaced by arginine, an amino acid with highly similar properties. This alteration has been reported in individuals from cohorts with Marfan syndrome or Marfan-like features; however, details were limited (Campens L et al. Orphanet J Rare Dis, 2015 Feb;10:9; Howarth R et al. Genet. Test., 2007;11:146-52). This variant was also detected in probands with bicuspid aortic valve, aortic dissection/dilation, and systemic features; however, other variants were also detected (Overwater E et al. Hum Mutat. 2018 09;39(9):1173-1192; Sticchi E et al. Biomed Res Int. 2018 Sep;2018:8386123). This alteration has also been seen in exome cohorts, but cardiovascular history was not provided (Dorschner MO et al. Am. J. Hum. Genet., 2013 Oct;93:631-40; Amendola LM et al. Genome Res., 2015 Mar;25:305-15). This amino acid position is highly 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.
Invitae	RCV000794919	SCV000934354	uncertain significance	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 2460 of the FBN1 protein (p.Lys2460Arg). This variant is present in population databases (rs144189837, gnomAD 0.01%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of Marfan syndrome and thoracic aortic disorders (PMID: 17627385, 21895641, 25644172, 29907982, 30255099). ClinVar contains an entry for this variant (Variation ID: 161239). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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.
CeGaT Center for Human Genetics Tuebingen	RCV000995332	SCV001149444	uncertain significance	not provided	2019-04-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001190175	SCV001357606	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with arginine at codon 2460 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 impact RNA splicing. However, an RNA study showed no abnormal splicing (PMID: 32123317). This variant has been reported in one individual affected with Marfan syndrome or Marfan-like phenotype (PMID: 17627385, 21895641) and in an individual affected with bicuspid aortic valve, a common congenital heart defect with increased prevalence of aortic dilatation/dissection (PMID: 30255099). This variant was also reported in an individual with aortic dissection and suspected hereditary thoracic aortic disease (PMID: 29907982) along with another individual who was affected with non-syndromic heritable thoracic aortic disorder (PMID: 25644172). This variant has also been identified in 20/282708 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.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000995332	SCV001449601	uncertain significance	not provided	2024-01-26	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000995332	SCV002051642	uncertain significance	not provided	2021-03-16	criteria provided, single submitter	clinical testing	No ACMG evidence could be applied applied
PreventionGenetics, part of Exact Sciences	RCV003422036	SCV004117282	uncertain significance	FBN1-related condition	2024-01-16	criteria provided, single submitter	clinical testing	The FBN1 c.7379A>G variant is predicted to result in the amino acid substitution p.Lys2460Arg. This variant was reported in multiple individuals with Marfan syndrome or related aortopathies (Howarth et al. 2007. PubMed ID: 17627385; Robinson et al. 2012. PubMed ID: 21895641; Campens et al. 2015. PubMed ID: 25644172; Growth et al. 2016. PubMed ID: 25812041). However, this variant was also found to co-occur with other rare variants in genes associated with Marfan syndrome phenotypes (Table S1, Overwater et al. 2018. PubMed ID: 29907982; Sticchi et al. 2018. PubMed ID: 30255099). This variant is reported in 0.015% of alleles in individuals of European (Non-Finnish) descent in gnomAD, which is more common than expected for disease-causing variant. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
CSER _CC_NCGL, University of Washington	RCV000148493	SCV000190199	uncertain significance	Marfan syndrome	2014-06-01	no assertion criteria provided	research
Center for Medical Genetics Ghent, University of Ghent	RCV000148493	SCV000787324	uncertain significance	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000995332	SCV001807828	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000995332	SCV001960083	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000995332	SCV001963973	uncertain significance	not provided		no assertion criteria provided	clinical testing