Submissions for variant NM_000267.3(NF1):c.3113+1G>A (rs267606599)

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000000373	SCV000753640	pathogenic	Neurofibromatosis, type 1	2019-10-15	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 23 of the NF1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with neurofibromatosis, type 1 (PMID: 26962827, 18484666, 16944272, 26969325, 25293717). ClinVar contains an entry for this variant (Variation ID: 345). Experimental studies have shown that this intronic change leads to skipping of exon 23 (also called exon 18 in the literature due to legacy nomenclature of NF1 exons) at transcription (PMID: 7633431). Donor and acceptor splice site variants 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.
GeneDx	RCV000680818	SCV000808265	pathogenic	not provided	2018-05-18	criteria provided, single submitter	clinical testing	The c.3113+1 G>A splice site variant has been previously reported in association with neurofibromatosis type 1 (Purandare et al., 1995; Emmerich et al., 2015). This variant destroys the canonical splice donor site in intron 23, and is expected to cause abnormal gene splicing. The variant is observed in 1/33570 (0.003%) alleles from individuals of Latino background in large population cohorts (Lek et al., 2016). Another splice variant at the same position, c.3113+1 G>T, has been reported in the Human Gene Mutation Database in association with neurofibromatosis type 1 (Stenson et al., 2014). In summary, we consider this variant to be pathogenic.
The Laboratory of Genetics and Metabolism, Hunan Children’s Hospital	RCV001009591	SCV001169692	pathogenic	Neurofibromatosis, type 1; Tibial pseudoarthrosis	2018-11-10	criteria provided, single submitter	research
Ambry Genetics	RCV001018701	SCV001179968	pathogenic	Hereditary cancer-predisposing syndrome	2020-08-13	criteria provided, single submitter	clinical testing	The c.3113+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 23 of the NF1 gene. This mutation has been detected in multiple individuals who fulfilled diagnostic criteria for neurofibromatosis type 1 (Upadhyaya M et al. Hum. Mutat., 2008 Aug;29:E103-11; Thomas L et al. Eur. J. Hum. Genet., 2012 Apr;20:411-9; Emmerich D et al. Eur. J. Hum. Genet., 2015 Jun;23:870-3; Hutter S et al. Hum. Genet., 2016 May;135:469-75). In addition to the clinical data presented in the literature, RNA studies have demonstrated that the alteration results in skipping of exon 23, leading to an in-frame deletion in a region critical to protein function (Purandare SM et al. Hum. Mol. Genet., 1995 Apr;4:767-8; Ars E et al. J. Med. Genet., 2003 Jun;40:e82; Pros E et al. Hum. Mutat., 2008 Sep;29:E173-93; Ambry internal data). This allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Centre for Mendelian Genomics,University Medical Centre Ljubljana	RCV000000373	SCV001368578	pathogenic	Neurofibromatosis, type 1	2020-04-02	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS3,PS4.
OMIM	RCV000000373	SCV000020517	pathogenic	Neurofibromatosis, type 1	1995-04-01	no assertion criteria provided	literature only