Submissions for variant NM_000138.5(FBN1):c.5369G>A (p.Arg1790Gln)

dbSNP: rs1555396428

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000773641	SCV000907335	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-10-04	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 1790 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 FBN1-related disorders in the literature. This variant has not been identified 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.
Blueprint Genetics	RCV000788925	SCV000928219	pathogenic	not provided	2019-02-12	criteria provided, single submitter	clinical testing
Invitae	RCV001868188	SCV002276832	uncertain significance	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-10-09	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1790 of the FBN1 protein (p.Arg1790Gln). This variant is not present in population databases (gnomAD no frequency). 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: 549272). 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.
GeneDx	RCV000788925	SCV004035847	uncertain significance	not provided	2023-03-17	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); 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); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 12938084)
PreventionGenetics, part of Exact Sciences	RCV004533458	SCV004116613	uncertain significance	FBN1-related disorder	2023-08-17	criteria provided, single submitter	clinical testing	The FBN1 c.5369G>A variant is predicted to result in the amino acid substitution p.Arg1790Gln. This variant was reported in an individual from a Marfan syndrome cohort (Table S1, Muiño-Mosquera et al. 2018. PubMed ID: 29875124). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant has conflicting interpretations of pathogenicity in ClinVar ranging from pathogenic to uncertain (http://www.ncbi.nlm.nih.gov/clinvar/variation/549272). A different nucleotide substitution affecting the same amino acid (p.Arg1790Pro) has been reported in an individual with Marfan syndrome (Loeys et al. 2001. PubMed ID: 11700157). Although we suspect that the c.5369G>A (p.Arg1790Gln) variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health	RCV000663777	SCV004814661	uncertain significance	Marfan syndrome	2023-10-23	criteria provided, single submitter	clinical testing	Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the calcium-binding EGF-like motif 29 domain of the FBN1 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant is rare in the general population and has been identified in 0/277264 chromosomes by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Center for Medical Genetics Ghent, University of Ghent	RCV000663777	SCV000787128	likely pathogenic	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing