Submissions for variant NM_000138.5(FBN1):c.7999G>A (p.Glu2667Lys)

gnomAD frequency: 0.00006  dbSNP: rs149062442

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000522146	SCV000052440	uncertain significance	not specified	2024-02-05	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.7999G>A (p.Glu2667Lys) results in a conservative amino acid change located in the EGF-like calcium-binding domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function.The variant allele was found at a frequency of 2e-05 in 250448 control chromosomes, predominantly at a frequency of 0.00012 within the African or African-American subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. This variant has been reported in the literature in individuals affected with features suggestive of Marfan Syndrome (Arnaud_2017). It was subsequently reported in individuals with fetal demise/multiple anomalies and short stature, respectively (example, Ahn_2021, Zhao_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Marfan Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34653508, 27582083, 33100332). ClinVar contains an entry for this variant (Variation ID: 36124). Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV000767117	SCV000617052	uncertain significance	not provided	2024-11-07	criteria provided, single submitter	clinical testing	Reported as a variant of uncertain significance in a 22+ week fetus with multiple anomalies (PMID: 33100332); In silico analysis indicates that this missense variant does not alter protein structure/function; Does not affect a cysteine or calcium-binding residue within an EGF-like domain or a TGF-binding protein domain of the FBN1 gene; cysteine substitutions in the EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (PMID: 12938084); This variant is associated with the following publications: (PMID: 34653508, Wilkerson2023[casereport], 12938084, 33100332, 27582083)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000522146	SCV000710903	uncertain significance	not specified	2017-05-22	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Glu2667Ly s variant in FBN1 has been reported in 1 individual from a consanguineous family with clinical features of Marfan syndrome and segregated with disease in 3 affe cted relatives, one of whom was homozygous for the variant but was not more seve rely affected (Arnaud 2016). This variant has also been reported in ClinVar (Var iation ID 36124). In addition, it has been identified in 1/66690 of European chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs149062442). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summa ry, while there is some suspicion for a pathogenic role, the clinical significan ce of the p.Glu2667Lys variant is uncertain.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000631962	SCV000753065	likely pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 2667 of the FBN1 protein (p.Glu2667Lys). This variant is present in population databases (rs149062442, gnomAD 0.02%). This missense change has been observed in individuals with clinical features of Marfan syndrome and/or aortic dissection (PMID: 27582083; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 36124). 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 with a negative predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001188432	SCV001355491	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-12-16	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 2667 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 homozygosity in an individual from a consanguineous Algerian family, who had clinical features of Marfan syndrome (PMID: 27582083). The proband's heterozygous father and daughter had aortic dilation, while the heterozygous mother was unaffected (PMID: 27582083). This variant has also been reported in a case of fetal demise with multiple anomalies (PMID: 33100332). This variant has been identified in 9/281854 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.
MGZ Medical Genetics Center	RCV002288522	SCV002579386	uncertain significance	Marfan syndrome	2021-08-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001188432	SCV002678598	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2024-03-26	criteria provided, single submitter	clinical testing	The p.E2667K variant (also known as c.7999G>A), located in coding exon 63 of the FBN1 gene, results from a G to A substitution at nucleotide position 7999. The glutamic acid at codon 2667 is replaced by lysine, an amino acid with similar properties. This variant was identified in the homozygous state in a 51-year-old female with aortic dilatation; it was also present in her father and daughter with aortic dilatation as well as her unaffected mother (Arnaud P et al. J. Med. Genet., 2017 02;54:100-103). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on available evidence to date, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002482916	SCV002796304	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	2021-12-17	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV002288522	SCV004844932	uncertain significance	Marfan syndrome	2024-07-10	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 2667 of the FBN1 protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in homozygosity in an individual from a consanguineous family, who had clinical features of Marfan syndrome (PMID: 27582083). The individual's heterozygous parent and sibling had aortic dilation, while the other heterozygous parent was unaffected (PMID: 27582083). This variant has also been reported in a case of fetal demise with multiple anomalies (PMID: 33100332) and in an individual affected with dilated cardiomyopathy (PMID: 37904629). This variant has been identified in 9/281854 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.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV002288522	SCV005438463	uncertain significance	Marfan syndrome	2024-12-18	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000767117	SCV005879960	uncertain significance	not provided	2024-11-19	criteria provided, single submitter	clinical testing	The FBN1 c.7999G>A; p.Glu2667Lys variant (rs149062442, ClinVar Variation ID: 36124) is reported in the literature in a homozygous individual from a consanguineous Algerian family who had features of Marfan syndrome, the homozygous individual did not exhibit more severe symptoms and the heterozygous father/daughter had aortic dilation, while the heterozygous mother was unaffected (Arnaud 2017). Additionally, this variant has been reported in an individual with idiopathic short stature but no other Marfan-like symptoms (Ahn 2022) and in one case of fetal demise (Zhao 2021). This variant is found in the general population with an overall allele frequency of 0.003% (9/281,854 alleles)) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.454). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Ahn J et al. Next-generation sequencing-based mutational analysis of idiopathic short stature and isolated growth hormone deficiency in Korean pediatric patients. Mol Cell Endocrinol. 2022 Mar 15;544:111489. PMID: 34653508. Arnaud P et al. Homozygous and compound heterozygous mutations in the FBN1 gene: unexpected findings in molecular diagnosis of Marfan syndrome. J Med Genet. 2017 Feb;54(2):100-103. PMID: 27582083. Zhao C et al. Exome sequencing analysis on products of conception: a cohort study to evaluate clinical utility and genetic etiology for pregnancy loss. Genet Med. 2021 Mar;23(3):435-442. PMID: 33100332.