Submissions for variant NM_000138.5(FBN1):c.643C>G (p.Arg215Gly)

gnomAD frequency: 0.00001  dbSNP: rs111687884

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001187334	SCV001354104	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-12-21	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glycine at codon 215 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 cardiovascular disorders in the literature. This variant has been identified in 4/251368 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001868302	SCV002155509	likely pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-12-18	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 215 of the FBN1 protein (p.Arg215Gly). This variant is present in population databases (rs111687884, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of FBN1-related conditions (Invitae; external communication). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 561296). 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%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics	RCV001187334	SCV002657426	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2018-05-21	criteria provided, single submitter	clinical testing	The p.R215G variant (also known as c.643C>G), located in coding exon 6 of the FBN1 gene, results from a C to G substitution at nucleotide position 643. The arginine at codon 215 is replaced by glycine, an amino acid with dissimilar properties. 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 alteration remains unclear.
GeneDx	RCV003313131	SCV004012476	uncertain significance	not provided	2023-07-06	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); 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); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12938084)
All of Us Research Program, National Institutes of Health	RCV000680523	SCV004823117	uncertain significance	Marfan syndrome	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glycine at codon 215 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 cardiovascular disorders in the literature. This variant has been identified in 4/251368 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.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000680523	SCV000807925	likely benign	Marfan syndrome	2018-06-01	flagged submission	clinical testing