Submissions for variant NM_000138.5(FBN1):c.5459G>A (p.Arg1820His)

gnomAD frequency: 0.00001  dbSNP: rs1340155407

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001176544	SCV001340563	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2025-03-17	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 1820 of the FBN1 protein. Computational prediction tool is inconclusive regarding the impact of this variant on protein structure and function. 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 2/251204 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	RCV001586023	SCV001812917	uncertain significance	not provided	2019-04-22	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Although located in a calcium-binding EGF-like domain of the FBN1 gene, it does not affect a cysteine residue within this domain; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (Collod-Beroud et al., 2003)
Institute of Human Genetics, University of Goettingen	RCV002246150	SCV002515885	uncertain significance	Marfan syndrome	2022-05-20	criteria provided, single submitter	clinical testing	For the following reasons, the FBN1 sequence variant found is assessed by us as a "variant of uncertain significance" (VUS): the mutation is already listed in ClinVar as a "variant of uncertain significance" (ClinVar: Variation ID: 918773; dbSNP: rs1340155407); a comparison with the gnomAD browser did not provide any evidence that this sequence change is a norm variant detectable also in non-affected individuals, the mutation occurs with a frequency of 0.0008% (gnomAD), and never in the homozygous state; the mutation is independently classified as deleterious by three (M-CAP, PolyPhen-2, MutationTaster) prediction programs. An autosomal dominant inheritance underlies the FBN1-associated diseases and an incomplete penetrance with variable expressivity is found, so that oligosymptomatic carriers may also occur. The above-mentioned FBN1 sequence variant is still classified by us as a "variant of uncertain significance" with unclear clinical relevance (class 3).
Ambry Genetics	RCV001176544	SCV002649722	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2021-11-18	criteria provided, single submitter	clinical testing	The p.R1820H variant (also known as c.5459G>A), located in coding exon 44 of the FBN1 gene, results from a G to A substitution at nucleotide position 5459. The arginine at codon 1820 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002491499	SCV002793230	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	2022-04-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002558822	SCV003241802	uncertain significance	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-02-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1820 of the FBN1 protein (p.Arg1820His). This variant is present in population databases (no rsID available, 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: 918773). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FBN1 protein function. 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.
All of Us Research Program, National Institutes of Health	RCV002246150	SCV004814655	uncertain significance	Marfan syndrome	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 1820 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 not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 2/251204 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.