ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.872A>C (p.Glu291Ala) (rs876660171)

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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 RCV000223188 SCV000277376 uncertain significance Hereditary cancer-predisposing syndrome 2015-07-21 criteria provided, single submitter clinical testing In silico models in agreement (benign);Insufficient or conflicting evidence
GeneDx RCV000479894 SCV000570800 uncertain significance not provided 2016-06-27 criteria provided, single submitter clinical testing This variant is denoted NF1 c.872A>C at the cDNA level, p.Glu291Ala (E291A) at the protein level, and results in the change of a Glutamic Acid to an Alanine (GAA>GCA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. NF1 Glu291Ala was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glutamic Acid and Alanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. NF1 Glu291Ala occurs at a position that is conserved across species and is not located in a known functional domain (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether NF1 Glu291Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000806878 SCV000946897 uncertain significance Neurofibromatosis, type 1 2020-01-14 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with alanine at codon 291 of the NF1 protein (p.Glu291Ala). The glutamic acid residue is moderately conserved and there is a moderate physicochemical difference between glutamic acid and alanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with NF1-related disease. ClinVar contains an entry for this variant (Variation ID: 233074). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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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