ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.989C>T (p.Ala330Val) (rs1555610898)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Human Genetics, Inc RCV000659974 SCV000781889 pathogenic Neurofibromatosis, type 1 2016-11-01 criteria provided, single submitter clinical testing
GeneDx RCV000680813 SCV000808259 pathogenic not provided 2018-01-19 criteria provided, single submitter clinical testing The c.989C>T variant in the NF1 gene has been reported in multiple individuals with features consistent with neurofibromatosis type 1 (Wimmer et al., 2007; Nemethova et al., 2013; Sabbagh et al., 2013). This variant is not observed in large population cohorts (Lek et al., 2016). Functional studies show c.989C>T activates a cryptic splice donor site that would result in a protein lacking 25 amino acid residues (Wimmer et al., 2007; Sabbagh et al., 2013). If c.989C>T does not alter splicing, it will result in the A330V missense change. The A330V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Based on the currently available information, we consider c.989C>T to be a pathogenic variant.
Invitae RCV000659974 SCV000938737 likely pathogenic Neurofibromatosis, type 1 2018-09-21 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 330 of the NF1 protein (p.Ala330Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with neurofibromatosis type 1 (PMID: 17311297, 23758643, 23913538). ClinVar contains an entry for this variant (Variation ID: 547578). Experimental studies have shown that this missense change leads to aberrant mRNA splicing (PMID: 23758643). This variant disrupts the p.Ala330 amino acid residue in NF1. Other variant that disrupts this residue have been observed in affected individuals (PMID: 17311297, 27322474), which suggests that this may be a clinically significant amino acid residue. 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.

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