Submissions for variant NM_001999.4(FBN2):c.2717G>A (p.Arg906His)

gnomAD frequency: 0.00010  dbSNP: rs370973542

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000476271	SCV000553187	likely benign	Congenital contractural arachnodactyly	2023-12-17	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000476271	SCV001318246	likely benign	Congenital contractural arachnodactyly	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
GeneDx	RCV001566251	SCV001789742	uncertain significance	not provided	2023-01-04	criteria provided, single submitter	clinical testing	Reported in two Dutch individuals with aortic aneurysm and/or dissection (Overwater et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Does not occur within a calcium-binding-EGF-like domain (Callewaert et al., 2009, Frederic et al., 2009); This variant is associated with the following publications: (PMID: 29907982)
Ambry Genetics	RCV002429546	SCV002744306	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-01-07	criteria provided, single submitter	clinical testing	The p.R906H variant (also known as c.2717G>A), located in coding exon 21 of the FBN2 gene, results from a G to A substitution at nucleotide position 2717. The arginine at codon 906 is replaced by histidine, an amino acid with highly similar properties. This variant was reported in two individuals from a thoracic aortic aneurysm and dissection (TAAD) cohort; however, clinical details were limited (Overwater E et al. Hum Mutat, 2018 09;39:1173-1192). This amino acid position is highly conserved in available 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.