Submissions for variant NM_000268.4(NF2):c.586C>T (p.Arg196Ter)

dbSNP: rs1555993336

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000554782	SCV000628875	pathogenic	Neurofibromatosis, type 2	2023-12-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg196*) in the NF2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NF2 are known to be pathogenic (PMID: 9643284, 16983642). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with neurofibromatosis type 2 (PMID: 7759081, 8797533, 11085592, 18033041). ClinVar contains an entry for this variant (Variation ID: 457921). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000599281	SCV000709957	pathogenic	not provided	2018-11-07	criteria provided, single submitter	clinical testing	The R196X nonsense variant in the NF2 gene has been reported previously in individuals diagnosed with or suspicious for neurofibromatosis type 2 (Joachim et al., 2001; Caltabiano et al., 2017). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R196X variant is not observed in large population cohorts (Lek et al., 2016). Based on currently available evidence, we consider R196X to be pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000554782	SCV000917898	pathogenic	Neurofibromatosis, type 2	2018-07-03	criteria provided, single submitter	clinical testing	Variant summary: NF2 c.586C>T (p.Arg196X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 246252 control chromosomes (gnomAD). The variant, c.586C>T, has been reported in the literature in multiple individuals affected with Neurofibromatosis Type 2 (Bonne_2016, Bourn_1995, Evans_1998). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
Mendelics	RCV000554782	SCV001141389	pathogenic	Neurofibromatosis, type 2	2019-05-28	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000599281	SCV001475232	pathogenic	not provided	2020-06-02	criteria provided, single submitter	clinical testing	The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data.
Genome-Nilou Lab	RCV000554782	SCV002045422	pathogenic	Neurofibromatosis, type 2	2021-11-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002358461	SCV002652675	pathogenic	Hereditary cancer-predisposing syndrome	2021-04-13	criteria provided, single submitter	clinical testing	The p.R196* pathogenic mutation (also known as c.586C>T), located in coding exon 6 of the NF2 gene, results from a C to T substitution at nucleotide position 586. This changes the amino acid from an arginine to a stop codon within coding exon 6. This alteration has been reported in numerous individuals with a clinical diagnosis of neurofibromatosis type 2 (Bourn D et al. Hum Genet. 1995 May;95:572-4; MacCollin M et al. Ann Neurol. 1996 Sep;40:440-5; Kluwe L et al. Neurogenetics. 2000 Sep;3:17-24; Evans DG et al. J Neurosurg. 2008 Jan;108:92-6; Plotkin SR et al. J Neurosurg Spine. 2011 Apr;14:543-7; Bonne N- et al. Childs Nerv Syst. 2016 Dec;32:2403-2413; Caltabiano R et al. Childs Nerv Syst. 2017 Jun;33:933-940; Waisberg V et al. Graefes Arch Clin Exp Ophthalmol. 2019 Jul;257:1453-1458). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Genetics and Molecular Pathology, SA Pathology	RCV000554782	SCV002761579	pathogenic	Neurofibromatosis, type 2	2019-07-31	criteria provided, single submitter	clinical testing