Submissions for variant NM_001042492.3(NF1):c.4369A>G (p.Lys1457Glu)

dbSNP: rs878853893

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000229110	SCV000284458	pathogenic	Neurofibromatosis, type 1	2024-11-23	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 1436 of the NF1 protein (p.Lys1436Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with neurofibromatosis type 1 (NF1) (PMID: 21354044, 23913538, 24789688). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 237563). 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%. RNA analysis provides insufficient evidence to determine the effect of this variant on NF1 splicing (internal data). This variant disrupts the p.Lys1436 amino acid residue in NF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22807134, 24789688). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002318966	SCV001183971	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2024-01-12	criteria provided, single submitter	clinical testing	The p.K1436E pathogenic mutation (also known as c.4306A>G), located in coding exon 32 of the NF1 gene, results from an A to G substitution at nucleotide position 4306. The lysine at codon 1436 is replaced by glutamic acid, an amino acid with similar properties. This alteration has been detected in three individuals meeting NIH diagnostic criteria for Neurofibromatosis type 1 (NF1) (Evans DG et al. EBioMedicine. 2016 May;7:212-20), one of which was a de novo occurrence (Valero MC et al. J Mol Diagn. 2011 Mar;13:113-22). In addition, this alteration was detected in two other individuals with features of NF1 (Sabbagh A et al. Hum. Mutat. 2013 Nov;34:1510-8; Xu W et al. Int. J. Mol. Med. 2014 Jul;34:53-60). Based on internal structural analysis and one additional study, this variant is anticipated to disrupt a loop region in the putative Ras-binding groove (Fu Y et al. J. Dermatol. 2018 Jun; Scheffzek K et al. Science. 1997 Jul;277(5324):333-8; Ambry Internal Analysis). A different alteration located at the same position, p.K1436E (c.4306A>C), was detected in two individuals with features of NF1 (Xu W et al. Int. J. Mol. Med. 2014 Jul;34:53-60; Thomas L et al. Hum. Mutat. 2012 Dec;33:1687-96). This amino acid position is highly conserved in available vertebrate species. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV001557248	SCV001778975	pathogenic	not provided	2022-09-27	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 9219684, 31487937, 29484149, 27322474, 29952103, 24789688, 23913538, 22807134, 32697994, 25486365, 21354044, 31776437)
Genome-Nilou Lab	RCV000229110	SCV002560046	pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV001557248	SCV004224661	likely pathogenic	not provided	2023-05-17	criteria provided, single submitter	clinical testing	PP2, PP3, PP4, PM2, PM5, PS2_moderate, PS4_moderate