ClinVar Miner

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

dbSNP: rs876660206
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Total submissions: 5
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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.
Invitae RCV000700494 SCV000829251 pathogenic Neurofibromatosis, type 1 2023-01-19 criteria provided, single submitter clinical testing This variant is not present in population databases (gnomAD no frequency). 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: 8437860, 17114577, 23047742). 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: 233115). 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. 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).
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 likely pathogenic Hereditary cancer-predisposing syndrome; Cardiovascular phenotype 2020-09-02 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.

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