ClinVar Miner

Submissions for variant NM_001042492.3(NF1):c.1062G>T (p.Lys354Asn)

dbSNP: rs1131691118
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV002014416 SCV002300016 likely pathogenic Neurofibromatosis, type 1 2021-04-02 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.1062G nucleotide in the NF1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 29673180). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. Nucleotide substitutions within 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, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with neurofibromatosis type 1 (PMID: 31766501, 30290804). This variant is not present in population databases (ExAC no frequency). This sequence change replaces lysine with asparagine at codon 354 of the NF1 protein (p.Lys354Asn). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and asparagine. This variant also falls at the last nucleotide of exon 9, which is part of the consensus splice site for this exon.
Medical Genetics, University of Parma RCV002014416 SCV002567800 pathogenic Neurofibromatosis, type 1 2022-08-17 criteria provided, single submitter clinical testing

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