Submissions for variant NM_001999.4(FBN2):c.3394G>A (p.Val1132Ile)

gnomAD frequency: 0.00021  dbSNP: rs138834515

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000513490	SCV000250104	likely benign	not provided	2021-04-14	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24205039, 32381728)
Ambry Genetics	RCV002310771	SCV000317899	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-05-26	criteria provided, single submitter	clinical testing	The p.V1132I variant (also known as c.3394G>A), located in coding exon 26 of the FBN2 gene, results from a G to A substitution at nucleotide position 3394. The valine at codon 1132 is replaced by isoleucine, an amino acid with highly similar properties. 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.
Illumina Laboratory Services, Illumina	RCV000310235	SCV000452610	uncertain significance	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae	RCV000310235	SCV000553172	likely benign	Congenital contractural arachnodactyly	2024-01-13	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000513490	SCV000603678	uncertain significance	not provided	2023-10-09	criteria provided, single submitter	clinical testing	The FBN2 c.3394G>A; p.Val1132Ile variant (rs138834515) is reported in the literature in a family affected with adolescent idiopathic scoliosis, although it was not demonstrated to be causative (Jiang 2020). This variant is found in the general population with an overall allele frequency of 0.02% (48/282800 alleles) in the Genome Aggregation Database. The valine at codon 1132 is highly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.431). However, due to limited information, the clinical significance of the p.Val1132Ile variant is uncertain at this time. References: Jiang et al. Exome sequencing analysis identifies frequent oligogenic involvement and FLNB variants in adolescent idiopathic scoliosis. J Med Genet. 2020 Jun;57(6):405-413. PMID: 32381728.
CeGaT Center for Human Genetics Tuebingen	RCV000513490	SCV000609175	uncertain significance	not provided	2021-10-01	criteria provided, single submitter	clinical testing
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000659611	SCV000781450	likely benign	Connective tissue disorder	2016-11-01	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000768222	SCV000898707	uncertain significance	Congenital contractural arachnodactyly; Macular degeneration, early-onset	2021-03-30	criteria provided, single submitter	clinical testing	FBN2 NM_001999.3 exon 26 p.Val1132Ile (c.3394G>A): This variant has not been reported in the literature and is present in 0.03% (7/19946) of East Asian alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/5-127674703-C-T). This variant is present in ClinVar (Variation ID:213228). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.