Submissions for variant NM_001999.4(FBN2):c.6959T>C (p.Met2320Thr)

gnomAD frequency: 0.00001  dbSNP: rs749681942

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000196115	SCV000250310	uncertain significance	not provided	2016-05-26	criteria provided, single submitter	clinical testing	The M2320T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The M2320T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, this substitution occurs within a calcium-binding EGF-like domain at a position where only amino acids with similar properties to Methionine are tolerated across species. Nevertheless, the M2320T variant does not affect a Cysteine residue within a calcium-binding EGF-like domain of the FBN2 gene. Cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with CCA (Collod-Beroud et al., 2003; Frederic et al., 2009). Furthermore, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Illumina Laboratory Services, Illumina	RCV001154748	SCV001316128	uncertain significance	Congenital contractural arachnodactyly	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Invitae	RCV001154748	SCV002143316	uncertain significance	Congenital contractural arachnodactyly	2021-10-20	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt FBN2 protein function. ClinVar contains an entry for this variant (Variation ID: 213425). This variant has not been reported in the literature in individuals affected with FBN2-related conditions. This variant is present in population databases (rs749681942, ExAC 0.001%). This sequence change replaces methionine with threonine at codon 2320 of the FBN2 protein (p.Met2320Thr). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and threonine.