Submissions for variant NM_000138.5(FBN1):c.1880G>A (p.Arg627His)

gnomAD frequency: 0.00004  dbSNP: rs746073643

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000485013	SCV000565835	uncertain significance	not provided	2018-02-23	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the FBN1 gene. The R627H variant has notbeen published as pathogenic or been reported as benign to our knowledge. However, a pathogenicvariant affecting the same residue (R627C) has been reported multiple times in association withMarfan syndrome, TAAD, and ectopia lentis (Halliday et al., 2002; Rommel et al., 2005; Jin et al.,2007; Stheneur et al., 2009; Attanasio et al., 2013; Campens et al., 2015). In addition, the R627Hvariant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000Genomes Consortium et al., 2015; Exome Variant Server). However, R627H is a conservative aminoacid substitution, which is not likely to impact secondary protein structure as these residues sharesimilar properties. This substitution occurs at a position where amino acids with similar properties toArginine are tolerated across species, and Histidine is the wild-type amino acid at this position in atleast two species. In silico analysis is inconsistent in its predictions as to whether or not the variant isdamaging to the protein structure/function. Furthermore, although the R627H variant occurs within acalcium-binding EGF-like domain of the FBN1 gene, it does not affect a Cysteine residue. Cysteinesubstitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missensechanges associated with Marfan syndrome (Collod-Beroud et al., 2003).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000803376	SCV000943243	likely benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-08-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001179088	SCV001343681	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-11-16	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 627 of the FBN1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 11/282840 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.
Ambry Genetics	RCV001179088	SCV002717666	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2020-03-27	criteria provided, single submitter	clinical testing	The p.R627H variant (also known as c.1880G>A), located in coding exon 15 of the FBN1 gene, results from a G to A substitution at nucleotide position 1880. The arginine at codon 627 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species; however, histidine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002506159	SCV002796911	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	2021-09-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226302	SCV003922534	likely benign	not specified	2024-07-08	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.1880G>A (p.Arg627His) results in a non-conservative amino acid change located in an EGF-like repeat (IPR000742) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was reported at an allele frequency (AF) of 0.00011 in the gnomAD database, predominantly within the on-Finnish European control individuals (AF: 0.00015). The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.3 fold of the estimated maximal expected allele frequency for a pathogenic variant in FBN1 causing Marfan Syndrome phenotype (0.00011). c.1880G>A has been reported in the literature in individuals affected with thoracic aortic aneurysms (e.g., Weerakkody_2018), however no supportive evidence of causality was provided. This report does not provide unequivocal conclusions about association of the variant with Marfan Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 29543232). ClinVar contains an entry for this variant (Variation ID: 418630). Based on the evidence outlined above, the variant was classified as likely benign.
All of Us Research Program, National Institutes of Health	RCV004002262	SCV004823025	uncertain significance	Marfan syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 627 of the FBN1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 11/282840 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.