Submissions for variant NM_001042492.3(NF1):c.6428-3C>A

dbSNP: rs374014162

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000579072	SCV000680723	uncertain significance	not provided	2017-11-27	criteria provided, single submitter	clinical testing	The c.6365-3 C>A variant has been published previously in association with neurofibromatosis type 1 (Wimmer et al., 2007). The variant is not observed in large population cohorts (Lek et al., 2016). Several in silico splice prediction models predict that c.6365-3 C>A damages the natural acceptor site and leads to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Institute of Human Genetics, Medical University Innsbruck	RCV001093652	SCV001250664	pathogenic	Neurofibromatosis, type 1	2020-01-20	criteria provided, single submitter	clinical testing
Invitae	RCV001093652	SCV001512165	likely pathogenic	Neurofibromatosis, type 1	2022-08-03	criteria provided, single submitter	clinical testing	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. This variant disrupts the c.6365-3 nucleotide in the NF1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 18546366, 24232412, 30308447; Invitae). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 42 or part of exon 42 and introduces a premature termination codon (PMID: 17311297, 32126153). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 488818). This variant has been observed in individual(s) with neurofibromatosis type 1 (PMID: 17311297). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 41 of the NF1 gene. It does not directly change the encoded amino acid sequence of the NF1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001779016	SCV002015058	uncertain significance	not specified	2021-10-25	criteria provided, single submitter	clinical testing	Variant summary: NF1 c.6365-3C>A alters a conserved 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: Four predict the variant weakens a 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing with an altered protein product resulting in skipping of exon 34 (Wimmer_2007). The variant was absent in 251068 control chromosomes. c.6365-3C>A has been reported in the literature in one individual affected with Neurofibromatosis Type 1 (Wimmer_2007). Due to the rarity of the variant, these population data do not allow any conclusion about variant significance. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation: two have determined this variant to be VUS and one has determined this variant to be pathogenic. Based on the evidence outlined above, the variant was classified as VUS - possibly pathogenic.
Medical Genetics, University of Parma	RCV001093652	SCV002567797	likely pathogenic	Neurofibromatosis, type 1	2022-08-17	criteria provided, single submitter	clinical testing