Submissions for variant NM_000138.5(FBN1):c.4750G>A (p.Glu1584Lys)

gnomAD frequency: 0.00029  dbSNP: rs148888513

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035210	SCV000058854	uncertain significance	not specified	2014-04-07	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The Gly1584Lys vari ant in FBN1 has been identified by our laboratory in 2 Hispanic individuals, one with a family history and one with clinical diagnosis of Marfan syndrome. This variant has also been identified in 1.8% (2/110) of Puerto Rican chromosomes by the 1000 Genomes Project (http://www.1000genomes.org; dbSNP rs148888513). Comput ational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. While this frequency suggests that thi s variant is more likely benign, the number of control individuals is too low to confidently rule out a disease-causing role. Additional information is needed t o fully assess its clinical significance.
GeneDx	RCV001703452	SCV000233836	uncertain significance	not provided	2024-03-20	criteria provided, single submitter	clinical testing	Identified in a patient with isolated thoracic aortic aneurysm with or without dissection (iTAAD) and in a patient with an inherited connective tissue disorder and eosinophilic esophagitis (PMID: 33824467, 23608731); Reported in two affected relatives from a Columbian family with non-syndromic unilateral cleft lip and palate who underwent exome sequencing (PMID: 27456059); Does not affect a cysteine residue within a calcium-binding EGF-like domain or a TGF-binding protein domain of the FBN1 gene; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (PMID: 12938084); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33824467, 23608731, 12938084, 27456059)
Ambry Genetics	RCV000777948	SCV000319249	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2024-01-09	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Fulgent Genetics, Fulgent Genetics	RCV000515425	SCV000611392	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	2017-05-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000632070	SCV000753173	likely benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-01-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000777948	SCV000914046	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2018-10-25	criteria provided, single submitter	clinical testing
Department of Vascular Biology, Beijing Anzhen Hospital	RCV001374849	SCV001439533	uncertain significance	Isolated thoracic aortic aneurysm	2018-09-01	criteria provided, single submitter	research
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002277122	SCV002566533	uncertain significance	Connective tissue disorder	2020-02-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000035210	SCV004813330	likely benign	not specified	2024-02-16	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.4750G>A (p.Glu1584Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.8e-05 in 1,603,250 control chromosomes (gnomAD v4.0), predominantly at a frequency of 0.0013 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 11.5-fold of the estimated maximal expected allele frequency for a pathogenic variant in FBN1 causing Aortopathy phenotype (0.00011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. The variant, c.4750G>A, has been reported in the literature in individuals affected with connective tissue disorders, including aortopathy, however no supporting evidence for causality was provided (e.g. Abonia_2013, Franken_2017, Li_2021). These reports do not provide unequivocal conclusions about association of the variant with Aortopathy. 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: 23608731, 28468757, 33824467). ClinVar contains an entry for this variant (Variation ID: 42370). Based on the evidence outlined above, the variant was classified as likely benign.