ClinVar Miner

Submissions for variant NM_001999.4(FBN2):c.1720A>G (p.Ile574Val) (rs768073096)

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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 RCV000246071 SCV000319319 uncertain significance Cardiovascular phenotype 2014-09-03 criteria provided, single submitter clinical testing The p.I574V variant (also known as c.1720A>G), located in coding exon 12 of the FBN2 gene<span style="background-color: initial;">in the cb EGF-like #05 domain<span style="background-color: initial;">, results from an A to G substitution at nucleotide position 1720. The isoleucine at codon 574 is replaced by valine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6,503 samples (13,006 alleles) with coverage at this position. This amino acid position is conserved in available vertebrate species, except for stickleback and medaka. In addition, this alteration is predicted to be possibly damaging<span style="background-color: initial;">by PolyPhen<span style="background-color: initial;">but tolerated by SIFT <em style="background-color: initial;">in silico<span style="background-color: initial;"> analyses.<span style="background-color: initial;">Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Fulgent Genetics,Fulgent Genetics RCV000765802 SCV000897192 uncertain significance Congenital contractural arachnodactyly; Macular degeneration, early-onset 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000810490 SCV000950693 uncertain significance Congenital contractural arachnodactyly 2020-04-21 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 574 of the FBN2 protein (p.Ile574Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs768073096, ExAC 0.005%). This variant has not been reported in the literature in individuals with FBN2-related disease. ClinVar contains an entry for this variant (Variation ID: 263857). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C0. The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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