Submissions for variant NM_001042492.3(NF1):c.204+1G>T

dbSNP: rs886039548

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000521162	SCV000617572	pathogenic	not provided	2021-05-20	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in an in-frame deletion of exon 2; Deletions involving coding exons of this gene are a known mechanism of disease (Stenson 2014); Observed in individuals with clinical features of neurofibromatosis type 1 (Fahsold 2000, Wimmer 2007, Witkowski 2020); This variant is associated with the following publications: (PMID: 26056819, 17311297, 10712197, 25525159, 30014477, 28717660, 30988082, 21354044, 12807981, 24789688, 25074460, 23913538, 31717729, 32107864)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000606260	SCV000712606	pathogenic	Neurofibromatosis, type 1	2016-10-27	criteria provided, single submitter	clinical testing	The c.204+1G>T variant in NF1 has been reported in 8 individuals with NF1 (Fahso ld 2000, Ars 2003, Wimmer 2007, Pros 2008, Valero 2011, Xu 2014, Pasmant 2015, Z hang 2015) and was absent from large population studies. In addition, this varia nt occurs in the invariant region (+/- 1/2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein . In vivo functional studies provide some evidence that the c.204+1G>T variant m ay impact protein function by creating a cryptic splice site that leads to skipp ing of exon 2 or at least a portion of exon 2 (Ars 2003, Wimmer 2007, Pros 2008) . In summary, this variant meets our criteria to be classified as pathogenic for NF1 in an autosomal dominant based upon functional evidence, absence from contr ols, and frequency in probands.
Invitae	RCV000606260	SCV000935226	pathogenic	Neurofibromatosis, type 1	2023-07-18	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 449419). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the NF1 protein in which other variant(s) (p.Leu43Pro) have been determined to be pathogenic (PMID: 28529006, 31370276; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Studies have shown that disruption of this splice site results in the activation of a cryptic splice site in exon 2 (PMID: 17311297). Disruption of this splice site has been observed in individuals with neurofibromatosis type 1 (PMID: 17311297, 21354044). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change affects a donor splice site in intron 2 of the NF1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in the loss of 35 amino acid residue(s), but is expected to preserve the integrity of the reading-frame.
Ambry Genetics	RCV002319015	SCV001174868	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2018-12-06	criteria provided, single submitter	clinical testing	The c.204+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 2 of the NF1 gene. This mutation has been detected in multiple patients with a clinical diagnosis of neurofibromatosis type 1 (NF1) and RNA splicing analysis has demonstrated aberrant splicing (Fahsold R et al. Am J Hum Genet. 2000 Mar;66(3):790-818; Wimmer K et al. Hum Mutat. 2007 Jun;28(6):599-612; Pros E et al. Hum Mutat. 2008 Sep;29(9):E173-93; Pasmant E et al. Eur J Hum Genet. 2015 May;23(5):596-601). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Genome-Nilou Lab	RCV000606260	SCV002561552	pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000521162	SCV004227784	likely pathogenic	not provided	2022-09-28	criteria provided, single submitter	clinical testing	PP4, PM2, PS4_moderate, PVS1_moderate