Submissions for variant NM_001042492.3(NF1):c.3113+1G>C

dbSNP: rs267606599

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics, University of Leipzig Medical Center	RCV001253362	SCV001429034	pathogenic	Neurofibromatosis, type 1	2018-11-06	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001253362	SCV001583236	pathogenic	Neurofibromatosis, type 1	2022-10-03	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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: 976156). Disruption of this splice site has been observed in individuals with neurofibromatosis type 1 (PMID: 7633431, 29498099). This variant is not present in population databases (gnomAD no frequency). 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).
GeneDx	RCV001724278	SCV002107245	pathogenic	not provided	2022-03-10	criteria provided, single submitter	clinical testing	Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with suspected or clinically diagnosed neurofibromatosis type 1 (Yoshida 2018, Assunto 2019); Also known as IVS18+1G>C; This variant is associated with the following publications: (PMID: 19738042, 22155606, 25486365, 2121369, 31730495, 29498099)
Genome-Nilou Lab	RCV001253362	SCV002559926	pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002322169	SCV002607851	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2022-05-23	criteria provided, single submitter	clinical testing	The c.3113+1G>C intronic pathogenic mutation results from a G to C 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 (Yoshida Y et al. J Dermatol, 2018 Mar;45:363-364; Assunto A et al. Orphanet J Rare Dis, 2019 11;14:261; Ambry internal data). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001724278	SCV001954378	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001724278	SCV001976166	pathogenic	not provided		no assertion criteria provided	clinical testing