Submissions for variant NM_001999.4(FBN2):c.6948C>A (p.Ile2316=)

dbSNP: rs17608368

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000117028	SCV000168512	benign	not specified	2013-02-21	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000234712	SCV000287276	benign	Congenital contractural arachnodactyly	2024-01-31	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000117028	SCV000308641	benign	not specified		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002310667	SCV000317359	benign	Familial thoracic aortic aneurysm and aortic dissection	2015-01-23	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	RCV000234712	SCV000452557	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000590588	SCV000603688	benign	not provided	2023-11-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590588	SCV000697901	benign	not provided	2017-03-22	criteria provided, single submitter	clinical testing	Variant summary: The FBN2 c.6948C>A (p.Ile2316Ile) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may eliminate an SRp40 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 0.0185658 (2252/121298 control chromosomes [40 homozygotes]), which is approximately 14853 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000117028	SCV000711372	benign	not specified	2013-04-04	criteria provided, single submitter	clinical testing	Ile2316Ile in exon 55 of FBN2: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 2.0% (169/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs17608368).
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000234712	SCV000743976	benign	Congenital contractural arachnodactyly	2014-10-10	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002277171	SCV002565955	benign	Ehlers-Danlos syndrome	2022-07-05	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002277172	SCV002566591	benign	Connective tissue disorder	2022-01-22	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000117028	SCV000151150	likely benign	not specified		no assertion criteria provided	clinical testing	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000234712	SCV000745926	benign	Congenital contractural arachnodactyly	2014-11-19	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000590588	SCV001798343	likely benign	not provided		no assertion criteria provided	clinical testing