ClinVar Miner

Submissions for variant NM_000268.4(NF2):c.1232G>A (p.Arg411His) (rs201214090)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000632640 SCV000753825 uncertain significance Neurofibromatosis, type 2 2020-05-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 411 of the NF2 protein (p.Arg411His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs201214090, ExAC 0.02%). This variant has not been reported in the literature in individuals with NF2-related disease. ClinVar contains an entry for this variant (Variation ID: 527695). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Fulgent Genetics,Fulgent Genetics RCV000765629 SCV000896954 uncertain significance Meningioma, familial; Neurofibromatosis, type 2; Schwannomatosis 1 2018-10-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV001010465 SCV001170667 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-07 criteria provided, single submitter clinical testing The p.R411H variant (also known as c.1232G>A), located in coding exon 12 of the NF2 gene, results from a G to A substitution at nucleotide position 1232. The arginine at codon 411 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001198705 SCV001369700 uncertain significance Meningioma, familial 2019-12-05 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3,BS2.
Broad Institute Rare Disease Group, Broad Institute RCV001249076 SCV001423027 uncertain significance not specified 2020-01-22 no assertion criteria provided curation The p.Arg411His variant in NF2 has not been previously reported in individuals with Neurofibromatosis but has been identified in 0.01181% (4/33872) of Latino chromosomes, 0.003403% (1/29382) of South Asian chromosomes, and 0.0009079% (1/110142) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD,; dbSNP rs201214090). This variant has also been reported as a VUS in ClinVar (Variation ID: 527695). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. One additional variant, resulting in a different amino acid change at the same position, p.Arg411Cys, has been reported as a VUS in association with disease in ClinVar (Variation ID: 567682). In summary, while the clinical significance of the p.Arg411His variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: BS1 (Richards 2015).

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