Submissions for variant NM_001999.4(FBN2):c.287_289del (p.Tyr96del)

dbSNP: rs555068280

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001705107	SCV000250269	uncertain significance	not provided	2023-04-13	criteria provided, single submitter	clinical testing	Has been reported in one patient with pulmonary nontuberculous mycobacteria (Szymanski et al., 2015); although members of this study cohort were evaluated for associated connective tissue features, no patient-specific clinical data or family member data were included for this variant; In silico analysis supports a deleterious effect on protein structure/function; In-frame deletion of a tyrosine residue at codon 96, in a non-repeat region; 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: 26038974)
Ambry Genetics	RCV000246013	SCV000318875	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2013-06-25	criteria provided, single submitter	clinical testing	There is insufficient or conflicting evidence for classification of this alteration.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000469776	SCV000563030	likely benign	Congenital contractural arachnodactyly	2024-12-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000246013	SCV000738961	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2021-09-03	criteria provided, single submitter	clinical testing	The c.287_289delACT variant (also known as p.Y96del) is located in coding exon 2 of the FBN2 gene. This variant results from an in-frame deletion of 3 nucleotides at positions 287 to 289. This results in the deletion of a tyrosine residue at codon 96. This variant was reported once in an exome pulmonary nontuberculous mycobacterial infection cohort; however, clinical details were limited (Szymanski EP et al. Am J Respir Crit Care Med, 2015 Sep;192:618-28). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003479056	SCV004223376	likely benign	not specified	2023-11-06	criteria provided, single submitter	clinical testing	Variant summary: FBN2 c.287_289delACT (p.Tyr96del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 0.00021 in 250414 control chromosomes. The observed variant frequency is approximately 169.32 fold of the estimated maximal expected allele frequency for a pathogenic variant in FBN2 causing Aortopathy phenotype (1.3e-06), strongly suggesting that the variant is benign. c.287_289delACT has been reported in the literature in a patient with pulmonary nontuberculous mycobacteria infection, without strong evidence for causality (Szymanksi_2015). This report does not provide unequivocal conclusions about association of the variant with Aortopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 26038974). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014: two classified the variant as VUS while one classified as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001705107	SCV005875607	uncertain significance	not provided	2024-06-10	criteria provided, single submitter	clinical testing	The FBN2 c.287_289del; p.Tyr96del variant (rs555068280, ClinVar Variation ID: 213385) is reported in the literature in one individual affected with pulmonary nontuberculous mycobacteria infection; however, disease association is unclear (Szymanski 2015). This variant is found in the general population with an overall allele frequency of 0.02% (57/281,814 alleles) in the Genome Aggregation Database (v2.1.1). This variant deletes a single tyrosine residue leaving the rest of the protein in-frame. Due to limited information, the clinical significance of this variant is uncertain at this time. References: Szymanski EP et al. Pulmonary Nontuberculous Mycobacterial Infection. A Multisystem, Multigenic Disease. Am J Respir Crit Care Med. 2015 Sep 1;192(5):618-28. PMID: 26038974.
PreventionGenetics, part of Exact Sciences	RCV003917787	SCV004730706	likely benign	FBN2-related disorder	2022-03-16	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).