Submissions for variant NM_001042492.3(NF1):c.3113+2T>G

dbSNP: rs876658997

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000213563	SCV000274932	pathogenic	Hereditary cancer-predisposing syndrome	2015-04-03	criteria provided, single submitter	clinical testing	The c.3113+2T>G intronic pathogenic mutation results from a T to G substitution two nucleotides after coding exon 23 in the NF1 gene. Another nucleotide change at this position, c.3113+2T>C, has been identified in a pt with clinical suspicionof NF1 and waspredicted to result in exon skipping (Pros E et al, Hum. Mutat. 2008 Sep; 29(9):E173-93). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, the c.3113+2T>G alteration is predicted to abolish the native donor splice site; however, direct evidence is unavailable. In addition to the clinical data presented in the literature, since alterations that disrupt the canonical splice donor site are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294).
Invitae	RCV000230814	SCV000284427	pathogenic	Neurofibromatosis, type 1	2023-12-23	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. 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). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with neurofibromatosis type I (Invitae). ClinVar contains an entry for this variant (Variation ID: 231169). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000230814	SCV000781971	likely pathogenic	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000230814	SCV002559929	pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000230814	SCV002579784	pathogenic	Neurofibromatosis, type 1	2021-12-22	criteria provided, single submitter	clinical testing