ClinVar Miner

Submissions for variant NM_001042492.3(NF1):c.3198-314G>A

dbSNP: rs2067116490
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001204931 SCV001376162 pathogenic Neurofibromatosis, type 1 2021-06-12 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant is associated with aberrant splicing, which introduces a premature termination codon (PMID: 21394830). The resulting mRNA is expected to undergo nonsense-mediated decay. This variant has been observed in individual(s) with neurofibromatosis type 1 (PMID: 21394830, Invitae). ClinVar contains an entry for this variant (Variation ID: 936187). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change falls in intron 24 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.
GeneDx RCV002249792 SCV002520146 likely pathogenic not provided 2022-05-16 criteria provided, single submitter clinical testing In silico analysis supports a deleterious effect on splicing. In a minigene assay, this variant produced full-length transcript as well as two aberrant transcripts (Fernandez-Rodriguez 2011); No data available from control populations to assess the frequency of this variant; Also known as IVS19a-314G>A; This variant is associated with the following publications: (PMID: 21394830, 24506781, 32408052, 34273915)
Genome-Nilou Lab RCV001204931 SCV002559937 likely pathogenic Neurofibromatosis, type 1 2022-03-15 criteria provided, single submitter clinical testing
Ambry Genetics RCV002322007 SCV002609691 likely pathogenic Hereditary cancer-predisposing syndrome; Cardiovascular phenotype 2020-03-04 criteria provided, single submitter clinical testing The c.3198-314G>A intronic likely pathogenic variant results from a G to A substitution 314 nucleotides before coding exon 25 in the NF1 gene. This alteration was first reported in an individual with a mild phenotype of neurofibromatosis type 1 (NF1) who was found to be mosaic for this alteration. In vitro functional studies found this alteration to affect splicing; however, the mutation was leaky and produced both truncated protein as well as normal protein (Fernandez-Rodriguez J et al. Hum Mutat. 2011;32(7):705-9). Using the BDGP and ESEfinder splice site prediction tools, this alteration creates an new alternate splice acceptor site that competes with the native splice acceptor site. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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