Submissions for variant NM_001042492.3(NF1):c.1185+1G>A

dbSNP: rs864622161

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000204498	SCV000259511	pathogenic	Neurofibromatosis, type 1	2021-10-20	criteria provided, single submitter	clinical testing	This variant is also known as IVS8+1G>A. Disruption of this splice site has been observed in individuals with neurofibromatosis type I (PMID: 10607834, 16835897, 18546366). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 10 of the NF1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in NF1 are known to be pathogenic (PMID: 10712197, 23913538). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the c.1185+1G nucleotide in the NF1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 8957181, 11726231). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 219572).
Medical Genetics, University of Parma	RCV000204498	SCV001218912	pathogenic	Neurofibromatosis, type 1	2019-12-20	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001091254	SCV001247181	pathogenic	not provided	2018-12-01	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000204498	SCV001479018	pathogenic	Neurofibromatosis, type 1	2020-10-26	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000204498	SCV002561637	pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000204498	SCV002579185	pathogenic	Neurofibromatosis, type 1	2022-04-19	criteria provided, single submitter	clinical testing
GeneDx	RCV001091254	SCV003918478	pathogenic	not provided	2023-04-03	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in an in-frame deletion of exon 10, confirmed by mRNA analysis in patient cells (Ars et al., 2000, Anastasaki et al., 2015, Giugliano et al., 2019); Deletions involving coding exons in this gene are frequently reported as pathogenic, regardless of frame prediction (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); A different pathogenic splice variant at this residue (c.1185+1 G>T) has been reported as pathogenic in the published literature in association with NF1-related neurofibromatosis (Horn et al., 1996); Also known as IVS8+1G>A; This variant is associated with the following publications: (PMID: 8957181, 25788518, 34427956, 25525159, 17726231, 10607834, 24361808, 16835897, 18546366, 32243842, 31370276)
Baylor Genetics	RCV003462367	SCV004198382	pathogenic	Juvenile myelomonocytic leukemia	2023-08-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004558450	SCV005048885	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2023-11-29	criteria provided, single submitter	clinical testing	The c.1185+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 10 of the NF1 gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ars E et al. Hum. Mol. Genet., 2000 Jan;9:237-47; Anastasaki C et al. Hum Mol Genet, 2015 Jun;24:3518-28; Ambry internal data). This mutation has been detected in multiple individuals with suspected or definite diagnosis of neurofibromatosis type 1 (NF1) (Anastasaki C et al. Hum Mol Genet, 2015 Jun;24:3518-28; Riva M et al. Genes Chromosomes Cancer, 2022 Jan;61:10-21; Ercolino T et al. Gene, 2014 Feb;536:332-5). In addition, another mutation at the same donor site (c.1185+2T>A) has been reported in individuals with clinical diagnosis of NF1 (Zhang J et al. Sci Rep, 2015 Jun;5:11291; Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.