ClinVar Miner

Submissions for variant NM_001999.4(FBN2):c.1423G>A (p.Gly475Ser) (rs200440156)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000246483 SCV000320513 uncertain significance Cardiovascular phenotype 2015-12-01 criteria provided, single submitter clinical testing The p.G475S variant (also known as c.1423G>A), located in coding exon 10 of the FBN2 gene, results from a G to A substitution at nucleotide position 1423. The glycine at codon 475 is replaced by serine, an amino acid with similar properties. This variant was previously reported in the SNPDatabase as rs200440156. Based on data from the 1000 Genomes Project, the A allele has an overall frequency of approximately 0.05% (1/2098) total alleles studied. The highest observed frequency was 0.86% (1/116) Mexican-American alleles. In population based cohorts in NHLBI ExomeSequencing Project (ESP), this variant was not observed in 6503 samples (13006 alleles) with coverage at this position.This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis.<span style="font-family:arial,sans-serif; font-size:10pt">Since supporting evidence is limited at this time, theclinical significance of this variant remains unclear.
Illumina Clinical Services Laboratory,Illumina RCV000322354 SCV000452639 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 RCV000322354 SCV000553200 uncertain significance Congenital contractural arachnodactyly 2016-10-05 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 475 of the FBN2 protein (p.Gly475Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs200440156, ExAC 0.01%) but has not been reported in the literature in individuals with a FBN2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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