ClinVar Miner

Submissions for variant NM_001999.4(FBN2):c.4102G>A (p.Val1368Met)

gnomAD frequency: 0.00005  dbSNP: rs762139261
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000756151 SCV000250291 uncertain significance not provided 2019-07-30 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Although located in a calcium-binding EGF-like domain of the FBN2 gene, it does not affect a cysteine residue within this domain; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN2-related disorders (Collod-Beroud et al., 2003; Frederic et al., 2009).; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID# 213407; Landrum et al., 2016)
Invitae RCV000529267 SCV000630233 uncertain significance Congenital contractural arachnodactyly 2023-12-29 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1368 of the FBN2 protein (p.Val1368Met). This variant is present in population databases (rs762139261, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with FBN2-related conditions. ClinVar contains an entry for this variant (Variation ID: 213407). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000756151 SCV000883875 uncertain significance not provided 2018-01-28 criteria provided, single submitter clinical testing The FBN2 c.4102G>A; p.Val1368Met variant (rs762139261), to our knowledge, is not reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the genome Aggregation Database (gnomAD) with an overall population frequency of 0.005% (identified on 14 out of 276,890 chromosomes) and is classified as a variant of unknown significance in ClinVar (ID: 213407).The valine at position 1368 is moderately conserved, considering 11 species, and computational analyses of the effects of the p.Val1368Met variant on protein structure and function predict a deleterious effect (SIFT: damaging, MutationTaster: disease causing, PolyPhen-2: probably damaging).The majority of pathogenic FBN2 missense variants are substitutions of cysteine residues within critical calcium-binding EGF-like domains (Collod-Beroud 2003), and while this variant is located in an EGF-like domain, it does not affect a conserved cysteine residue. Based on the available information, the clinical significance of the p.Val1368Met variant cannot be determined with certainty.
CeGaT Center for Human Genetics Tuebingen RCV000756151 SCV001154507 uncertain significance not provided 2019-03-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV002321790 SCV002626891 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2019-05-20 criteria provided, single submitter clinical testing The p.V1368M variant (also known as c.4102G>A), located in coding exon 32 of the FBN2 gene, results from a G to A substitution at nucleotide position 4102. The valine at codon 1368 is replaced by methionine, an amino acid with highly similar properties, and is located in a cbEGF-like domain. This amino acid position is highly 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.
Fulgent Genetics, Fulgent Genetics RCV002485301 SCV002778857 uncertain significance Congenital contractural arachnodactyly; Macular degeneration, early-onset 2021-11-03 criteria provided, single submitter clinical testing

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