Submissions for variant NM_000138.5(FBN1):c.6449G>A (p.Arg2150His)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002361821	SCV002656797	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2019-04-01	criteria provided, single submitter	clinical testing	The p.R2150H variant (also known as c.6449G>A), located in coding exon 52 of the FBN1 gene, results from a G to A substitution at nucleotide position 6449. The arginine at codon 2150 is replaced by histidine, an amino acid with highly similar properties, and is located in the cbEGF-like #32 domain. This variant was detected in a proband with aortic dissection (Tan L et al. Hum. Mol. Genet., 2017 12;26:4814-4822), and in a proband with systemic connective tissue findings whose reportedly unaffected parent also had the variant (Overwater E et al. Hum. Mutat., 2018 Sep;39:1173-1192). A cysteine substitution at this codon (p.R2150C, c.6448C>T) was detected in an individual with some Marfan syndrome-like features who did not meet Ghent criteria (Turner CL et al. Am. J. Med. Genet. A, 2009 Feb;149A:161-70). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003103300	SCV003462233	likely pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-01-02	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 2150 of the FBN1 protein (p.Arg2150His). 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 FBN1-related conditions (PMID: 28973303, 29907982, 34498425). ClinVar contains an entry for this variant (Variation ID: 1753578). 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.Arg2150 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. 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.
GeneDx	RCV003443042	SCV004167776	uncertain significance	not provided	2023-04-28	criteria provided, single submitter	clinical testing	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; 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); This variant is associated with the following publications: (PMID: 12938084, 29907982, 34498425, 28973303)