Submissions for variant NM_000138.5(FBN1):c.2743G>A (p.Glu915Lys)

dbSNP: rs746834413

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000455431	SCV000539153	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 TAAD proband
Labcorp Genetics (formerly Invitae), Labcorp	RCV000699635	SCV000828355	uncertain significance	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-09-30	criteria provided, single submitter	clinical testing	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. 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 not expected to disrupt FBN1 protein function. ClinVar contains an entry for this variant (Variation ID: 402849). This missense change has been observed in individual(s) with an acute dissection of the aorta (PMID: 17418587). This variant is present in population databases (rs746834413, gnomAD 0.0009%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 915 of the FBN1 protein (p.Glu915Lys).
Color Diagnostics, LLC DBA Color Health	RCV001525732	SCV001735916	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-06-14	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 915 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 thoracic aortic aneurysm and aortic dissection (PMID: 17418587). This variant has not been identified 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	RCV000995344	SCV001810783	uncertain significance	not provided	2019-11-04	criteria provided, single submitter	clinical testing	Reported in association with aortic aneurysm but additional clinical information was not provided (Waldmuller et al., 2007); Not observed in large population cohorts (Lek et al., 2016); Located in a calcium-binding EGF-like domain of the FBN1 gene but does not affect a cysteine residue; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar as a variant of uncertain significance but additional evidence is not available (ClinVar Variant ID# 402849; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 17418587)
Fulgent Genetics, Fulgent Genetics	RCV002481359	SCV002776841	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	2021-10-14	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004000602	SCV004814879	uncertain significance	Marfan syndrome	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 915 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 thoracic aortic aneurysm and aortic dissection (PMID: 17418587). This variant has not been identified 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.
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	RCV004783784	SCV005397295	uncertain significance	Weill-Marchesani syndrome 2, dominant	2023-12-04	criteria provided, single submitter	clinical testing	This sequence variant is a single nucleotide substitution (G>A) at coding position 2743 of the FBN1 gene that results in a glutamic acid to lysine amino acid change at residue 915 of the FBN1 encoded fibrillin-1 protein. The Glu915 residue falls in the fourteenth calcium-binding epidermal growth factor-like domain which is critical to the proper processing and secretion of fibrillin-1 (PMID: 10486319). This is a previously reported variant (ClinVar) that has been observed in an individual suspected of having a FBN1-related disorder (PMID: 17418587). This variant is absent from the gnomAD population database (0 of approximately 250,000 alleles). Multiple bioinformatic tools predict that this glutamic acid to lysine amino acid change would be damaging, and the glutamic acid residue is strongly conserved across the vertebrate species examined. Studies examining the functiol consequence of this variant have not been published, to our knowledge. At this time, there is insufficient evidence to determine if this variant is pathogenic or benign. Therefore, we consider this a variant of uncertain significance. ACMG Criteria: PM1, PM2, PP3