ClinVar Miner

Submissions for variant NM_001042492.3(NF1):c.3834C>G (p.Asn1278Lys)

dbSNP: rs1135402850
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Medical Genetics, University of Parma RCV000497120 SCV000588770 likely pathogenic Neurofibromatosis, type 1 2022-08-17 criteria provided, single submitter clinical testing
Invitae RCV000497120 SCV000824252 pathogenic Neurofibromatosis, type 1 2023-10-17 criteria provided, single submitter clinical testing This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 1278 of the NF1 protein (p.Asn1278Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with neurofibromatosis type 1 (PMID: 28961165). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 431630). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NF1 protein function. Experimental studies have shown that this missense change affects NF1 function (PMID: 12787671). For these reasons, this variant has been classified as Pathogenic.
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV000497120 SCV001479253 likely pathogenic Neurofibromatosis, type 1 2020-10-26 criteria provided, single submitter clinical testing
GeneDx RCV001575189 SCV001802128 likely pathogenic not provided 2023-09-26 criteria provided, single submitter clinical testing Published functional studies demonstrate slightly lower NF1 catalytic efficiency and affinity for RAS compared to wild-type but lack statistical significance (Ahmadian et al., 2003); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 12787671, 28961165, 25486365, 22807134, Martorana2022[CaseReport])
Genome-Nilou Lab RCV000497120 SCV002560000 likely pathogenic Neurofibromatosis, type 1 2022-03-15 criteria provided, single submitter clinical testing

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