Submissions for variant NM_001999.4(FBN2):c.460A>G (p.Met154Val)

gnomAD frequency: 0.00001  dbSNP: rs878854475

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000226698	SCV000287265	uncertain significance	Congenital contractural arachnodactyly	2024-06-16	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 154 of the FBN2 protein (p.Met154Val). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individuals with FBN2-related conditions (PMID: 26133393; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 239085). 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 with a negative predictive value of 80%. 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.
Ambry Genetics	RCV002310822	SCV000318707	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-05-03	criteria provided, single submitter	clinical testing	The p.M154V variant (also known as c.460A>G), located in coding exon 4 of the FBN2 gene, results from an A to G substitution at nucleotide position 460. The methionine at codon 154 is replaced by valine, an amino acid with highly similar properties. In one study, this alteration was detected in an individual with aortic dilation (Zarate YA et al. Genet. Med., 2016 Apr;18:356-63). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV001770194	SCV001992670	uncertain significance	not provided	2022-09-09	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Although located in a calcium-binding EGF-like domain of the FBN2 gene, it does not substitute or introduce a cysteine residue (Callewaert et al., 2009; Frederic et al., 2009); Not located within exons 24-33, where the majority of pathogenic variants reported to date occur (Callewaert et al., 2009, Frederic et al., 2009); This variant is associated with the following publications: (PMID: 26133393, 19006240, 18767143)
Fulgent Genetics, Fulgent Genetics	RCV002478855	SCV002792652	uncertain significance	Congenital contractural arachnodactyly; Macular degeneration, early-onset	2021-10-12	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003947766	SCV004760073	uncertain significance	FBN2-related disorder	2023-12-28	no assertion criteria provided	clinical testing	The FBN2 c.460A>G variant is predicted to result in the amino acid substitution p.Met154Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.