ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.4278G>C (p.Gln1426His) (rs876660206)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000220491 SCV000277424 uncertain significance Hereditary cancer-predisposing syndrome 2015-07-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Insufficient or conflicting evidence
Invitae RCV000700494 SCV000829251 pathogenic Neurofibromatosis, type 1 2018-07-24 criteria provided, single submitter clinical testing This sequence change replaces glutamine with histidine at codon 1426 of the NF1 protein (p.Gln1426His). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with NF1-related disease (Invitae). This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333) and personal communication (PMID: 23656349). ClinVar contains an entry for this variant (Variation ID: 233115). 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"). Variants that disrupt the p.Gln1426 amino acid residue in NF1 have been observed in affected individuals (PMID: 8437860, 17114577, 23047742). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.

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