ClinVar Miner

Submissions for variant NM_001042492.3(NF1):c.7458-3C>G

dbSNP: rs1158267419
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000681414 SCV000808877 uncertain significance not provided 2018-07-13 criteria provided, single submitter clinical testing The c.7395-3C>G variant has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.7395-3C>G variant is not observed in large population cohorts (Lek et al., 2016). Several in silico splice prediction models predict that c.7395-3C>G damages or destroys the splice acceptor site in intron 49, 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.
Ambry Genetics RCV002422464 SCV001188742 uncertain significance Hereditary cancer-predisposing syndrome; Cardiovascular phenotype 2023-07-26 criteria provided, single submitter clinical testing The c.7395-3C>G intronic variant results from a C to G substitution 3 nucleotides upstream from coding exon 50 in the NF1 gene. This variant has been reported in one individual who was suspected of having a NF1 diagnosis but did not meet clinical criteria (Palma Milla C et al. Ann. Hum. Genet., 2018 11;82:425-436). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may result in the creation or strengthening of a novel splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV001344498 SCV001538557 uncertain significance Neurofibromatosis, type 1 2024-10-10 criteria provided, single submitter clinical testing This sequence change falls in intron 49 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 present in population databases (no rsID available, gnomAD 0.003%). This variant has been observed in individual(s) with NF1-related conditions (PMID: 30014477). ClinVar contains an entry for this variant (Variation ID: 561955). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). RNA analysis performed to evaluate the impact of this variant on mRNA splicing indicates it does not significantly alter splicing (internal data). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Genome-Nilou Lab RCV001344498 SCV002561086 uncertain significance Neurofibromatosis, type 1 2022-03-15 criteria provided, single submitter clinical testing

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