Submissions for variant NM_000138.5(FBN1):c.2861G>A (p.Arg954His)

dbSNP: rs112911555

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181469	SCV000233771	uncertain significance	not provided	2023-09-25	criteria provided, single submitter	clinical testing	Identified in an adult with skeletal and ocular features of Marfan syndrome without cardiac involvement (Sylen et al., 2009); Observed as a homozygous variant in a child with clinical features of Marfan syndrome; the heterozygous father was described as unaffected, while the heterozygous mother was described as having features suggestive of LeriWeill dyschondrosteosis (Nayak et al., 2021); 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; Does not affect a cysteine residue within a calcium-binding EGF-like domain or a TGF-binding protein 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); This variant is associated with the following publications: (PMID: 19159394, 33436942, 12938084)
Blueprint Genetics	RCV000208533	SCV000263899	likely pathogenic	Marfan syndrome	2015-10-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001192095	SCV000318124	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2015-10-29	criteria provided, single submitter	clinical testing	The p.R954H variant (also known as c.2861G>A), located in coding exon 24 of the FBN1 gene, results from a G to A substitution at nucleotide position 2861. The arginine at codon 954 is replaced by histidine, an amino acid with highly similar properties. In one study, p.R954H was detected in a 58-year-old female patient with positive wrist and thumb signs, joint hypermobility, highly arched palate with crowding of teeth, ectopia lentis, and dural ectasia. The novel alteration was reported to be familial and located in the TGF-beta like #3 module (Söylen B et al, Clin. Genet. 2009 Mar; 75(3):265-70). This variant was previously reported in the SNPDatabase as rs112911555, but was not reported in population based cohorts in the following databases: NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project. In the ESP, this variant was not observed in 6494 samples (12988 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV001192095	SCV001360068	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2022-09-22	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 954 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 performed for this variant. This variant has been reported in four individuals affected with Marfan syndrome (PMID: 12938084, 19159394, 33436942). One of the probands was homozygote and the parents were heterozygous carriers with limited clinical information available. This variant has also been reported in an individual with a history of aortic dissection (communication with an external laboratory; ClinVar SCV000263899.2). This variant has been identified in 1/251154 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg954Cys, is known to be pathogenic (Clinvar variation ID 495582), indicating that arginine at this position is important for FBN1 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic.
Invitae	RCV001205432	SCV001376689	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-12-04	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 954 of the FBN1 protein (p.Arg954His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with clinical features of Marfan syndrome in the heterozygous and homozygous state (PMID: 19159394, 33436942; Invitae). ClinVar contains an entry for this variant (Variation ID: 200005). 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%. This variant disrupts the p.Arg954 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001797666	SCV002041890	uncertain significance	not specified	2022-09-06	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.2861G>A (p.Arg954His) results in a non-conservative amino acid change in the encoded protein sequence. Five 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 251154 control chromosomes. c.2861G>A has been reported in the literature in individuals affected with Marfan Syndrome (Soylen_2009, Nayak_2021). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments: two reporting the variant as likely pathogenic and the remaining four reporting it as uncertain signficance. Another variant affecting the same codon (p.Arg954Cys), has been classifed as pathogenic by our laboratory. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Center for Medical Genetics Ghent, University of Ghent	RCV000208533	SCV000786899	likely pathogenic	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing