Submissions for variant NM_001042492.3(NF1):c.2990+5G>A

dbSNP: rs1555614464

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000632339	SCV000753516	pathogenic	Neurofibromatosis, type 1	2025-01-26	criteria provided, single submitter	clinical testing	This sequence change falls in intron 22 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 or undergoing testing for neurofibromatosis type 1 (PMID: 17311297, 21520333; internal data). ClinVar contains an entry for this variant (Variation ID: 527465). 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. This variant disrupts the c.2990+5G nucleotide in the NF1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 26740943). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000632339	SCV000781968	likely pathogenic	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001756045	SCV002005061	likely pathogenic	not provided	2022-09-14	criteria provided, single submitter	clinical testing	Observed in individuals reported to have neurofibromatosis type 1 (Wimmer et al., 2007); Not observed in large population cohorts (gnomAD); In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Also known as IVS17+5G>A; This variant is associated with the following publications: (PMID: 17576681, 9536098, 26740943, 17311297, LOVD, 35595873)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000632339	SCV003928897	likely pathogenic	Neurofibromatosis, type 1	2023-04-14	criteria provided, single submitter	clinical testing	Variant summary: NF1 c.2990+5G>A alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a canonical 5' donor site. One predict the variant no significant impact on splicing. At least one publication reports experimental evidence supporting an impact on splicing, finding an under-representation of the variant transcript allele relative to the wildtype allele using pyrosequencing (Brinckmann_2007), which is consistent with NMD following a frameshift. The variant was absent in 249736 control chromosomes (gnomAD). c.2990+5G>A has been reported in the literature in individuals affected with Neurofibromatosis Type 1 (Wimmer_2007, Brinckmann_2007). These data indicate that the variant is likely to be associated with disease. Three submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Ambry Genetics	RCV004559262	SCV005047650	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2023-06-29	criteria provided, single submitter	clinical testing	The c.2990+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 22 in the NF1 gene. This nucleotide position is highly conserved in available vertebrate species. This variant has been determined to be the result of a de novo mutation or germline mosaicism in one individual with Neurofibromitosis type 1 (External Communication). This alteration has also been observed in at least one individual with a personal and/or family history that is consistent with NF1-related disease (Bianchessi D. et al Mol Genet Genomic Med 2015 Nov;3(6):513-25). RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
NHS Central & South Genomic Laboratory Hub	RCV000632339	SCV005068230	pathogenic	Neurofibromatosis, type 1	2024-07-01	criteria provided, single submitter	clinical testing