Submissions for variant NM_001042492.3(NF1):c.6855C>G (p.Tyr2285Ter)

gnomAD frequency: 0.00001  dbSNP: rs772295894

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000508444	SCV000604465	pathogenic	not provided	2017-11-08	criteria provided, single submitter	clinical testing
Invitae	RCV000558457	SCV000628735	pathogenic	Neurofibromatosis, type 1	2023-11-02	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr2264*) in the NF1 gene. RNA analysis indicates that this premature translational stop signal induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs772295894, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with neurofibromatosis type 1 (PMID: 9385374, 17311297, 23668869, 23913538, 24232412). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 439973). Studies have shown that this premature translational stop signal results in skipping of exon 45, but is expected to preserve the integrity of the reading-frame (PMID: 9385374, 16870183, 22925204). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002314887	SCV000664447	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2021-12-13	criteria provided, single submitter	clinical testing	The c.6792C>G pathogenic mutation (also known as p.Y2264*), located in coding exon 45 of the NF1 gene, results from a C to G substitution at nucleotide position 6792. This changes the amino acid from a tyrosine to a stop codon within coding exon 45. This mutation has been reported in multiple patients with clinical features of neurofibromatosis type 1 (Messiaen L et al. Hum Genet, 1997 Nov;101:75-80; Wimmer K et al. Hum Mutat, 2007 Jun;28:599-612; Ko JM et al. Pediatr Neurol, 2013 Jun;48:447-53; Stewart DR et al. Genet Med, 2014 Jun;16:448-59; Whitworth J et al. JAMA Oncol, 2016 Mar;2:373-9). In addition, this mutation was detected as de novo in individuals with neurofibromatosis type 1 or epileptic encephalopathy (Sabbagh A et al. Hum Mutat, 2013 Nov;34:1510-8; Hamdan FF et al. Am J Hum Genet, 2017 Nov;101:664-685; Wang X et al. Genes Chromosomes Cancer, 2018 01;57:19-27). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. However, multiple RNA studies have demonstrated that this mutation primarily disrupts exonic splicing enhancer, leading to skipping of exon 45 (Messiaen L et al. Hum Genet, 1997 Nov;101:75-80; Baralle M et al. FEBS Lett, 2006 Aug;580:4449-56; Hernández-Imaz E et al. Clin Genet, 2013 May;83:462-6; Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000558457	SCV000782088	pathogenic	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000508444	SCV000890282	pathogenic	not provided	2021-09-01	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect on splicing (Messiaen 1997, Messiaen 2000, Baralle 2006); This variant is associated with the following publications: (PMID: 26659639, 16479075, 10862084, 23913538, 29100083, 30530636, 9385374, 22925204, 23668869, 22664653, 31370276, 18503770, 28891274, 24676943, 29625052, 16944272, 19142971, 24789688, 29122587, 16870183, 25525159, 24232412, 17311297)
Genome-Nilou Lab	RCV000558457	SCV002560216	pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing