Submissions for variant NM_001042492.3(NF1):c.4341G>C (p.Gln1447His)

dbSNP: rs876660206

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000220491	SCV000277424	likely pathogenic	Hereditary cancer-predisposing syndrome	2015-07-24	criteria provided, single submitter	clinical testing	The p.Q1426H variant (also known as c.4278G>C), located in coding exon 32 of the NF1 gene, results from a G to C substitution at nucleotide position 4278. The glutamine at codon 1426 is replaced by histidine, an amino acid with highly similar properties. This variant was detected in an individual with a clinical diagnosis of neurofibromatosis type 1 (Giugliano T et al. Genes (Basel), 2019 07;10:). Based on internal structural analysis, Q1426H is mildly destabilizing to the local structure of the NF1-RAS binding interface and more disruptive than known pathogenic variants on the same interface (Scheffzek K et al. EMBO J., 1998 Aug;17:4313-27; Ahmadian MR et al. J. Mol. Biol., 2003 Jun;329:699-710). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000700494	SCV000829251	pathogenic	Neurofibromatosis, type 1	2024-08-01	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 1426 of the NF1 protein (p.Gln1426His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with NF1-related disease (PMID: 21520333, 23656349; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 233115). 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 with a positive predictive value of 95%. This variant disrupts the p.Gln1426 amino acid residue in NF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8437860, 17114577, 23047742). 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.
Genome-Nilou Lab	RCV000700494	SCV002560045	likely pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
GeneDx	RCV002280112	SCV002568765	likely pathogenic	not provided	2022-08-15	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: 8437860, 23656349, 31370276, 35885913, 22807134, 33794220)
Ambry Genetics	RCV002327094	SCV002631595	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2025-03-05	criteria provided, single submitter	clinical testing	The p.Q1426H pathogenic mutation (also known as c.4278G>C), located in coding exon 32 of the NF1 gene, results from a G to C substitution at nucleotide position 4278. The glutamine at codon 1426 is replaced by histidine, an amino acid with highly similar properties. This variant was reported in individual(s) with features consistent with neurofibromatosis type 1 (Giugliano T et al. Genes (Basel). 2019 07;10; Napolitano F et al. Genes (Basel). 2022 Jun;13:; Bell JM et al. J Pediatr. 2021 Jul;234:134-141.e5; Ambry internal data). Based on internal structural analysis, Q1426H is mildly destabilizing to the local structure of the NF1-RAS binding interface and more disruptive than known pathogenic variants on the same interface (Scheffzek K et al. EMBO J. 1998 Aug;17:4313-27; Ahmadian MR et al. J. Mol. Biol. 2003 Jun;329:699-710). This variant was not reported in population-based 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 variant is interpreted as a disease-causing mutation.