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

dbSNP: rs1135402850

Total submissions: 6

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
Labcorp Genetics (formerly Invitae), Labcorp	RCV000497120	SCV000824252	pathogenic	Neurofibromatosis, type 1	2024-11-21	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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt NF1 protein function with a positive predictive value of 95%. 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
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001575189	SCV005624578	likely pathogenic	not provided	2024-07-26	criteria provided, single submitter	clinical testing	The NF1 c.3834C>G (p.Asn1278Lys) variant has been reported in the published literature in a neurofibromatosis patient in the apparent de novo state (PMID:28961165 (2017)). One experimental study showed in vitro changes in activity consistent with disruption of function, though further research is required to validate these findings (PMID: 12787671 (2003)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic.