ClinVar Miner

Submissions for variant NM_000268.4(NF2):c.1271G>T (p.Arg424Leu)

dbSNP: rs751182657
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000558170 SCV000628844 uncertain significance Neurofibromatosis, type 2 2023-11-24 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 424 of the NF2 protein (p.Arg424Leu). This variant is present in population databases (rs751182657, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with NF2-related conditions. ClinVar contains an entry for this variant (Variation ID: 457891). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NF2 protein function with a negative predictive value of 80%. 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.
Molecular Genetics, Royal Melbourne Hospital RCV000558170 SCV002503649 uncertain significance Neurofibromatosis, type 2 2021-04-09 criteria provided, single submitter clinical testing This sequence change is predicted to replace arginine with leucine at codon 424 of the NF2 protein (p.(Arg424Leu)). The arginine residue is evolutionarily conserved (100 vertebrates, UCSC), and is located in the coiled-coil domain. There is a moderate physicochemical difference between arginine and leucine. The variant is present in a large population cohort at a frequency of 0.002% (5/246,382 alleles, 0 homozygotes in gnomAD v2.1). It has been reported as a variant of uncertain significance (ClinVar). Multiple lines of computational evidence have conflicting predictions for the missense substitution (2/6 algorithms predict deleterious). Based on the classification scheme RMH Modified ACMG Guidelines v1.3.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE . Following criteria are met: none.
Ambry Genetics RCV002377021 SCV002687205 benign Hereditary cancer-predisposing syndrome 2022-01-24 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GenomeConnect - Invitae Patient Insights Network RCV000558170 SCV001749323 not provided Neurofibromatosis, type 2 no assertion provided phenotyping only Variant interpreted as Uncertain significance and reported on 09-29-2017 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

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