Submissions for variant NM_000138.5(FBN1):c.1615C>T (p.Arg539Trp)

gnomAD frequency: 0.00001  dbSNP: rs752999845

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001177822	SCV001342094	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-09-21	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 539 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with FBN1-related disorders in the literature. This variant has been identified in 3/251250 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001255570	SCV001432056	uncertain significance	not specified	2020-08-10	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.1615C>T (p.Arg539Trp) results in a non-conservative amino acid change located in the EGF-like calcium-binding domain (IPR001881) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251250 control chromosomes (gnomAD). 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.1615C>T in individuals affected with Marfan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One ClinVar submitter (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001875861	SCV002160522	uncertain significance	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-12-06	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 539 of the FBN1 protein (p.Arg539Trp). This variant is present in population databases (rs752999845, gnomAD 0.003%). 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: 919582). 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 expected to disrupt FBN1 protein function with a positive predictive value of 95%. 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.
Fulgent Genetics, Fulgent Genetics	RCV002480599	SCV002792449	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	2022-02-08	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004006415	SCV004823039	uncertain significance	Marfan syndrome	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 539 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 reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 3/251250 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.
GeneDx	RCV004590131	SCV005081348	uncertain significance	not provided	2023-06-08	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge