ClinVar Miner

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

dbSNP: rs786204157
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Total submissions: 4
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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
Labcorp Genetics (formerly Invitae), Labcorp RCV000660055 SCV004296759 pathogenic Neurofibromatosis, type 1 2023-04-22 criteria provided, single submitter clinical testing 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). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with NF1-related conditions (PMID: 26969325). ClinVar contains an entry for this variant (Variation ID: 428987). 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. 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. For these reasons, this variant has been classified as Pathogenic.

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