Submissions for variant NM_001999.4(FBN2):c.2099C>T (p.Thr700Ile)

gnomAD frequency: 0.00001  dbSNP: rs773667668

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000200116	SCV000250166	uncertain significance	not provided	2023-07-07	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); Does not occur within a calcium-binding-EGF-like domain (Callewaert et al., 2009, Frederic et al., 2009); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18767143)
Illumina Laboratory Services, Illumina	RCV001151277	SCV001312393	uncertain significance	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, 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	RCV001151277	SCV002122279	likely benign	Congenital contractural arachnodactyly	2023-08-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002415837	SCV002725078	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2020-03-27	criteria provided, single submitter	clinical testing	The p.T700I variant (also known as c.2099C>T), located in coding exon 16 of the FBN2 gene, results from a C to T substitution at nucleotide position 2099. The threonine at codon 700 is replaced by isoleucine, an amino acid with similar properties, and is located in the TGFB #02 domain. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000200116	SCV003834022	uncertain significance	not provided	2022-06-08	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003401065	SCV004112002	uncertain significance	FBN2-related condition	2023-02-21	criteria provided, single submitter	clinical testing	The FBN2 c.2099C>T variant is predicted to result in the amino acid substitution p.Thr700Ile. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0031% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-127705024-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.