Submissions for variant NM_001999.4(FBN2):c.3296G>A (p.Arg1099His)

gnomAD frequency: 0.00009  dbSNP: rs202050092

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000198639	SCV000250188	uncertain significance	not provided	2021-12-21	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; 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 FBN2 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 FBN2 related disorders (Frederic et al., 2009); Reported in ClinVar (ClinVar Variant ID# 213305; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 26582918)
Ambry Genetics	RCV002310786	SCV000317881	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2021-01-25	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Illumina Laboratory Services, Illumina	RCV000364863	SCV000452611	likely benign	Congenital contractural arachnodactyly	2018-01-13	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.
Invitae	RCV000364863	SCV000630217	likely benign	Congenital contractural arachnodactyly	2024-01-22	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002277524	SCV002565908	uncertain significance	Ehlers-Danlos syndrome	2019-11-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330566	SCV004039319	likely benign	not specified	2023-08-24	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000198639	SCV004698863	uncertain significance	not provided	2024-02-01	criteria provided, single submitter	clinical testing