ClinVar Miner

Submissions for variant NM_001999.4(FBN2):c.2252A>C (p.Glu751Ala) (rs147610681)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000438877 SCV000518443 uncertain significance not provided 2018-06-07 criteria provided, single submitter clinical testing The E751A variant has not been published in association with a FBN2-related disorder or been reported as benign to our knowledge. However, this variant has been reported as a variant of uncertain significance in ClinVar by another clinical laboratory (SCV000630198.1; Landrum et al., 2016). The E751A variant is observed in 0.013% (16/125694) of alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). Nevertheless, the E751A variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect.
Invitae RCV000526169 SCV000630198 uncertain significance Congenital contractural arachnodactyly 2017-04-20 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with alanine at codon 751 of the FBN2 protein (p.Glu751Ala). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and alanine. This variant is present in population databases (rs147610681, 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: "Benign"; 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.
Fulgent Genetics,Fulgent Genetics RCV000765801 SCV000897191 uncertain significance Congenital contractural arachnodactyly; Macular degeneration, early-onset 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000526169 SCV001312392 uncertain significance Congenital contractural arachnodactyly 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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