Submissions for variant NM_000138.5(FBN1):c.6025G>A (p.Glu2009Lys)

gnomAD frequency: 0.00001  dbSNP: rs773204216

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181697	SCV000234000	uncertain significance	not provided	2014-10-31	criteria provided, single submitter	clinical testing	p.Glu2009Lys (GAG>AAG): c.6025 G>A in exon 49 of the FBN1 gene (NM_000138.4) A variant of unknown significance has been identified in the FBN1 gene. The E2009K variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The E2009K variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Missense mutations in nearby residues (C2000S, C2011G, D2013Y) have been reported in association with Marfan syndrome, supporting the functional importance of this region of the protein. Additionally, the E2009K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved across species. Consequently, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in TAAD panel(s).
Ambry Genetics	RCV001182484	SCV000317365	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2019-04-14	criteria provided, single submitter	clinical testing	The p.E2009K variant (also known as c.6025G>A), located in coding exon 48 of the FBN1 gene, results from a G to A substitution at nucleotide position 6025. The glutamic acid at codon 2009 is replaced by lysine, an amino acid with similar properties. This amino acid position is poorly 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000557669	SCV000627948	likely benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-01-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001182484	SCV001347946	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-05-08	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 2009 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 affected with Marfan syndrome (DOI:10.15690/vsp.v15i2.1536). This variant has been identified in 1/251152 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.
Fulgent Genetics, Fulgent Genetics	RCV002492804	SCV002780961	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	2021-08-20	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000181697	SCV004129807	uncertain significance	not provided	2022-12-01	criteria provided, single submitter	clinical testing	FBN1: PP2
All of Us Research Program, National Institutes of Health	RCV003996704	SCV004814611	uncertain significance	Marfan syndrome	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 2009 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 affected with Marfan syndrome (DOI:10.15690/vsp.v15i2.1536). This variant has been identified in 1/251152 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.