Submissions for variant NM_000268.4(NF2):c.169C>T (p.Arg57Ter)

dbSNP: rs121434259

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255708	SCV000322362	pathogenic	not provided	2023-02-07	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16612978, 22760943, 21492294, 33067351, 8379998, 25525159, 9643284, 8655144, 12011146, 18554169, 15609345, 10771486, 23196945, 23921927, 10850863, 31273341)
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000660130	SCV000782121	pathogenic	Neurofibromatosis, type 2	2016-11-01	criteria provided, single submitter	clinical testing
Invitae	RCV000660130	SCV000945759	pathogenic	Neurofibromatosis, type 2	2023-11-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg57*) 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: 8379998, 8882871, 9884492, 18033041, 26073919). ClinVar contains an entry for this variant (Variation ID: 3285). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000660130	SCV001362183	pathogenic	Neurofibromatosis, type 2	2019-08-13	criteria provided, single submitter	clinical testing	Variant summary: NF2 c.169C>T (p.Arg57X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251490 control chromosomes. c.169C>T has been reported in the literature in multiple individuals affected with Neurofibromatosis Type 2 (Rouleau_1993, Kluwe_1996, Evans_1998, Goutagny_2012) . 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 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar (after 2014) and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab	RCV000660130	SCV002045420	pathogenic	Neurofibromatosis, type 2	2021-11-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002399307	SCV002714072	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-08	criteria provided, single submitter	clinical testing	The p.R57* pathogenic mutation (also known as c.169C>T), located in coding exon 2 of the NF2 gene, results from a C to T substitution at nucleotide position 169. This changes the amino acid from an arginine to a stop codon within coding exon 2. This mutation has been detected in multiple patients with Neurofibromatosis type 2 (NF2) (Rouleau GA et al. Nature, 1993 Jun;363:515-21; Kluwe L et al. Hum Genet, 1996 Nov;98:534-8; Evans DG et al. J Med Genet, 1998 Jun;35:450-5; Plotkin SR et al. J Neurosurg Spine, 2011 Apr;14:543-7; Goutagny S et al. Neuro Oncol, 2012 Aug;14:1090-6; Barrett VJ et al. J Neuroophthalmol, 2012 Dec;32:329-31; Pasmant E et al. Neurochirurgie, 2018 Nov;64:335-341; Lascelles K et al. Dev Med Child Neurol, 2018 12;60:1285-1288; Evans DG et al. Genet Med, 2020 01;22:53-59; Teranishi Y et al. J Med Genet, 2021 10;58:701-711). 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.
OMIM	RCV000003446	SCV000023604	pathogenic	Meningioma	1995-03-01	no assertion criteria provided	literature only
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000255708	SCV001957450	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000255708	SCV001973212	pathogenic	not provided		no assertion criteria provided	clinical testing