Submissions for variant NM_001042492.3(NF1):c.5311A>G (p.Lys1771Glu)

dbSNP: rs1131691103

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000492200	SCV000581303	likely pathogenic	Hereditary cancer-predisposing syndrome	2016-02-06	criteria provided, single submitter	clinical testing	The p.K1771E variant (also known as c.5311A>G, c.5248A>G and p.K1750E), located in coding exon 38 of the NF1 gene, results from an A to G substitution at nucleotide position 5311. The lysine at codon 1771 is replaced by glutamic acid, an amino acid with similar properties. This variant has been determined to be the result of a de novo mutation or germline mosaicism in one individual with NF1-related features tested in our laboratory. This variant has been reported as de novo in one individual from a cohort of patients with a clinical diagnosis or symptoms of NF1 (van Minkelen R et al. Clin. Genet., 2014 Apr;85:318-27). In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000632446	SCV000753627	pathogenic	Neurofibromatosis, type 1	2024-09-17	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 1750 of the NF1 protein (p.Lys1750Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of neurofibromatosis type 1 and neurofibromatosis-Noonan syndrome (PMID: 23656349; externalcommunication, internal data). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 428982). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NF1 protein function. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000680829	SCV000808277	pathogenic	not provided	2025-01-29	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; This variant is associated with the following publications: (PMID: 23656349, 21520333)
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000632446	SCV001478942	likely pathogenic	Neurofibromatosis, type 1	2020-10-26	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV002063855	SCV002495862	pathogenic	Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis	2022-02-08	criteria provided, single submitter	clinical testing	This variant has been reported in the literature as de novo in one individual with a clinical diagnosis or suspicion of Neurofibromatosis 1 (van Minkelen 2014 PMID:23656349). This variant has also been identified by multiple laboratories in several individuals with features suggestive of or consistent with Neurofibromatosis 1, and was determined to be de novo in at least one individual (ClinVar Variation ID:428982; inter-laboratory communications). Additionally, this variant is absent from large control databases. In summary, this variant is classified as pathogenic.
Ambry Genetics	RCV002341164	SCV002645391	likely pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2023-08-19	criteria provided, single submitter	clinical testing	The p.K1750E variant (also known as c.5248A>G), located in coding exon 37 of the NF1 gene, results from an A to G substitution at nucleotide position 5248. The lysine at codon 1750 is replaced by glutamic acid, an amino acid with similar properties. This variant has been determined to be the result of a de novo mutation or germline mosaicism in one individual with NF1-related features tested in our laboratory. This variant has been reported as de novo in one individual from a cohort of patients with a clinical diagnosis or symptoms of NF1 (van Minkelen R et al. Clin. Genet. 2014 Apr;85:318-27). This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.