Submissions for variant NM_000138.5(FBN1):c.7455T>G (p.Asp2485Glu)

gnomAD frequency: 0.00014  dbSNP: rs377272529

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001185037	SCV001351167	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2020-01-16	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glutamic acid at codon 2485 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 not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 13/282454 chromosomes (13/24966 African 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001299487	SCV001488580	uncertain significance	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2022-06-05	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 2485 of the FBN1 protein (p.Asp2485Glu). This variant is present in population databases (rs377272529, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with FBN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 923954). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
GeneDx	RCV001576296	SCV001803453	uncertain significance	not provided	2023-01-19	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002469349	SCV002765928	uncertain significance	not specified	2022-11-28	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.7455T>G (p.Asp2485Glu) results in a conservative amino acid change located in the EGF-like calcium-binding domain (IPR001881) of 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 3.6e-05 in 251060 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.7455T>G in individuals affected with Marfan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV002491543	SCV002790020	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	2021-12-03	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001576296	SCV004184455	uncertain significance	not provided	2023-11-01	criteria provided, single submitter	clinical testing	FBN1: PM5, PP3
All of Us Research Program, National Institutes of Health	RCV004008508	SCV004816763	uncertain significance	Marfan syndrome	2023-06-28	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glutamic acid at codon 2485 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 not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 13/282454 chromosomes (13/24966 African 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.