ClinVar Miner

Submissions for variant NM_001999.4(FBN2):c.3430G>A (p.Glu1144Lys) (rs200060005)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000248484 SCV000320662 uncertain significance Cardiovascular phenotype 2015-12-16 criteria provided, single submitter clinical testing The p.E1144K variant (also known as c.3430G>A), located in coding exon 26 of the FBN2 gene, results from a G to A substitution at nucleotide position 3430. The glutamic acid at codon 1144 is replaced by lysine, an amino acid with similar properties. This variant is found in anEGF-likecalcium-binding domain in the FBN2 gene.This variant was described toco-segregatewith early onset macular dystrophyin five relatives in one family (RatnapriyaR et al.HumMolGenet. 2014;23(21):5827-3).This variant was previously reported in the SNPDatabase as rs200060005. Based on data fromExAC, the Aallele was reported in 5of 121262(0.004%) total alleles (ExomeAggregation Consortium (ExAC), Cambridge, MA (URL: http://exac.broadinstitute.org) [Accessed December 15, 2015]).This variant was not reported in population-based cohorts in the following databases: NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project. In the ESP, this variant was not observed in 6503samples (13006alleles) with coverage at this position.This amino acid position is not well conserved in available 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 variantremains unclear.
Invitae RCV000468154 SCV000553206 uncertain significance Congenital contractural arachnodactyly 2017-07-10 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 1144 of the FBN2 protein (p.Glu1144Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs200060005, ExAC 0.007%). This variant has been reported in a single family affected with early-onset macular degeneration (PMID: 24899048). ClinVar contains an entry for this variant (Variation ID: 161445). 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: "Benign"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000680529 SCV000807932 uncertain significance Connective tissue disease 2018-06-01 criteria provided, single submitter clinical testing
OMIM RCV000148948 SCV000195868 pathogenic Macular degeneration, early-onset 2014-11-01 no assertion criteria provided literature only

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