ClinVar Genomic variation as it relates to human health

p.Gly2351Ser (GGC>AGC): c.7051 G>A in exon 58 of the FBN1 gene (NM_000138.4)The G2351S variant in the FBN1 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. The G2351S variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. G2351S is a non-conservative amino acid substitution as these residues differ in polarity, charge, size and/or other properties and is more likely to impact secondary structure. However, mutations in nearby residues have not been reported in association with Marfan syndrome indicating this region of the protein may tolerate change. Additionally, the G2351 residue is only well conserved in mammals, and in silico algorithms yielded conflicting results regarding the effect of G2351S on protein structure/function. With the clinical and molecular information available at this time, we cannot definitively determine if G2351S is a disease-causing mutation or a rare benign variant. The variant is found in TAAD panel(s).

Variant summary: FBN1 c.7051G>A (p.Gly2351Ser) results in a non-conservative amino acid change located in the TB domain (IPR017878) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 250838 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7051G>A has been reported in the literature in at least one individual diagnosed with aortic dissection (Sun_2019). This report does not provide unequivocal conclusions about association of the variant with Marfan Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

This missense variant replaces glycine with serine at codon 2351 of the FBN1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 4/250838 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

This missense variant replaces glycine with serine at codon 2351 of the FBN1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 4/250838 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

The p.G2351S variant (also known as c.7051G>A), located in coding exon 57 of the FBN1 gene, results from a G to A substitution at nucleotide position 7051. The glycine at codon 2351 is replaced by serine, an amino acid with similar properties. This alteration was reported in a sporadic coronary artery dissection cohort (Sun Y et al. J Am Coll Cardiol, 2019 Jul;74:167-176). This amino acid position is not well conserved in available vertebrate species, and serine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.