Submissions for variant NM_001042492.3(NF1):c.7970+5G>A

dbSNP: rs1567627286

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001290815	SCV001478976	likely pathogenic	Neurofibromatosis, type 1	2024-07-16	criteria provided, single submitter	clinical testing	This missense variant is located within 5 nucleotides of an intron/exon splicing junction. In silico prediction programs predict that this variant may affect splicing. However, this prediction has not been confirmed by RNA functional studies. It has been reported previously in individuals with Neurofibromatosis type 1 (PMIDs: 15146469, 25074460). This variant was reported to have occurred de novo in at least one individual. This variant has not been observed in population controls of the Genome Aggregation Database (gnomAD). Based on the evidence above, this variant is classified as likely pathogenic (ACMG criteria - PS4_Moderate, PM2, PM6, PP3, PP5).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001290815	SCV001575146	likely pathogenic	Neurofibromatosis, type 1	2024-01-01	criteria provided, single submitter	clinical testing	This sequence change falls in intron 53 of the NF1 gene. It does not directly change the encoded amino acid sequence of the NF1 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of NF1-related conditions (PMID: 15146469, 25074460; Invitae). ClinVar contains an entry for this variant (Variation ID: 996409). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx	RCV001586113	SCV001811295	likely pathogenic	not provided	2020-09-11	criteria provided, single submitter	clinical testing	Intronic +5 splice site variant in a gene for which loss-of-function is a known mechanism of disease, and splice predictors support a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 15146469)