Submissions for variant NM_001999.4(FBN2):c.8733C>G (p.Leu2911=)

gnomAD frequency: 0.02500  dbSNP: rs34383505

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000125088	SCV000168528	benign	not specified	2013-07-12	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
PreventionGenetics, part of Exact Sciences	RCV000125088	SCV000308662	benign	not specified		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002310704	SCV000317326	benign	Familial thoracic aortic aneurysm and aortic dissection	2015-09-06	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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	RCV000304034	SCV000452527	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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000304034	SCV000563024	benign	Congenital contractural arachnodactyly	2025-02-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590340	SCV000697907	benign	not provided	2017-03-29	criteria provided, single submitter	clinical testing	Variant summary: The FBN2 c.8733C>G (p.Leu2911Leu) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. The variant does not lie within a known functional domain and one in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing and ESE finder predicts that this variant may create an SF2/ASF ESE site at the locus. However, these predictions have yet to be confirmed by functional studies. This variant was found in the large control database ExAC at a frequency of 0.0077117 (936/121374 control chromosomes [26 homozygotes]), which is approximately 6169 times the estimated maximal expected allele frequency of a pathogenic FBN2 variant (0.0000013), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. To our knowledge, the variant of interest has not been reported in affected individuals via publications, nor has it been evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000590340	SCV001158706	benign	not provided	2023-10-14	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002277268	SCV002565991	benign	Ehlers-Danlos syndrome	2022-06-14	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002277269	SCV002566610	benign	Connective tissue disorder	2020-11-24	criteria provided, single submitter	clinical testing