ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.7307A>G (p.His2436Arg) (rs863224664)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000198278 SCV000254510 uncertain significance Neurofibromatosis, type 1 2018-11-30 criteria provided, single submitter clinical testing This sequence change replaces histidine with arginine at codon 2436 of the NF1 protein (p.His2436Arg). The histidine residue is moderately conserved and there is a small physicochemical difference between histidine and arginine. 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: 216410). 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, 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.
Ambry Genetics RCV000570451 SCV000663062 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-10 criteria provided, single submitter clinical testing Insufficient evidence
GeneDx RCV000681024 SCV000808475 uncertain significance not provided 2017-03-27 criteria provided, single submitter clinical testing This variant is denoted NF1 c.7307A>G at the cDNA level, p.His2436Arg (H2436R) at the protein level, and results in the change of a Histidine to an Arginine (CAT>CGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. NF1 His2436Arg was not observed at a significant frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Histidine and Arginine share similar properties, this is considered a conservative amino acid substitution. NF1 His2436Arg occurs at a position that is conserved across species and is not located in a known functional domain. In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether NF1 His2436Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

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