Submissions for variant NM_001042492.3(NF1):c.4340A>C (p.Gln1447Pro)

dbSNP: rs786204157

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000492775	SCV000581308	likely pathogenic	Hereditary cancer-predisposing syndrome	2016-03-29	criteria provided, single submitter	clinical testing	The p.Q1447Pvariant (also known as c.4340A>C, p.Q1426P, andc.4277A>C), located in coding exon 32 of the NF1 gene, results from an A to C substitution at nucleotide position 4277. The glutamine at codon 1426 is replaced by proline, an amino acid with similar properties. This alteration (referred to asp.Q1426P)has been reported in the literature in an individual meeting the NIH clinical criteria for NF1(Hutter S et al, Hum. Genet. 2016 Mar. Epub ahead of print). In addition, another alteration at the same codon (p.Q1426R) has been reported in an individual with Watson syndrome, an NF1-related disorder (Ben-Shachar S et al, Eur. J. Hum. Genet. 2013 May; 21(5):535-9). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6500 samples (13000 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. 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.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000660055	SCV000782019	pathogenic	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000660055	SCV002560044	likely pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Invitae	RCV000660055	SCV004296759	pathogenic	Neurofibromatosis, type 1	2023-04-22	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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: 23913538, 26969325; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 428987). This missense change has been observed in individual(s) with NF1-related conditions (PMID: 26969325). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 1426 of the NF1 protein (p.Gln1426Pro).