Submissions for variant NM_000138.5(FBN1):c.2582G>A (p.Arg861Gln)

gnomAD frequency: 0.00002  dbSNP: rs794728328

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181687	SCV000233990	uncertain significance	not provided	2020-04-10	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Does not affect a cysteine residue within a calcium-binding EGF-like 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 (Collod-Beroud et al., 2003); Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV001314005	SCV001504516	uncertain significance	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-04-29	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 200181). This variant has not been reported in the literature in individuals affected with FBN1-related conditions. This variant is present in population databases (rs794728328, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 861 of the FBN1 protein (p.Arg861Gln).
Fulgent Genetics, Fulgent Genetics	RCV002503706	SCV002814047	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	2021-08-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003398907	SCV004122436	uncertain significance	not specified	2023-10-31	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.2582G>A (p.Arg861Gln) results in a conservative amino acid change located in the TB domain (IPR017878) 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 4e-06 in 251450 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.2582G>A in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV003528149	SCV004357437	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-03-07	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 861 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 1/251450 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.
All of Us Research Program, National Institutes of Health	RCV003996703	SCV004833225	uncertain significance	Marfan syndrome	2023-08-15	criteria provided, single submitter	clinical testing