ClinVar Miner

Submissions for variant NM_001042492.3(NF1):c.3827G>C (p.Arg1276Pro)

dbSNP: rs137854556
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000000381 SCV000753612 pathogenic Neurofibromatosis, type 1 2023-06-13 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 353). This missense change has been observed in individual(s) with neurofibromatosis type 1 (PMID: 9668168). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 1276 of the NF1 protein (p.Arg1276Pro). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg1276 amino acid residue in NF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9302992, 10712197, 15060124, 16479075, 19221814, 22807134, 23668869, 27322474). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects NF1 function (PMID: 9668168, 16513807, 26635368). 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.
Center for Human Genetics, Inc, Center for Human Genetics, Inc RCV000000381 SCV000782002 pathogenic Neurofibromatosis, type 1 2016-11-01 criteria provided, single submitter clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV002267796 SCV002550896 pathogenic not provided 2023-08-15 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000000381 SCV002559998 pathogenic Neurofibromatosis, type 1 2022-03-15 criteria provided, single submitter clinical testing
Ambry Genetics RCV002354143 SCV002623237 likely pathogenic Hereditary cancer-predisposing syndrome; Cardiovascular phenotype 2022-07-11 criteria provided, single submitter clinical testing The p.R1276P variant (also known as c.3827G>C), located in coding exon 28 of the NF1 gene, results from a G to C substitution at nucleotide position 3827. The arginine at codon 1276 is replaced by proline, an amino acid with dissimilar properties. This alteration has been identified in multiple individuals diagnosed with neurofibromatosis type 1 (Klose A et al. Hum Mol Genet, 1998 Aug;7:1261-8; Fahsold R et al. Am J Hum Genet, 2000 Mar;66:790-818; Koczkowska M et al. Hum Mutat, 2020 01;41:299-315). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
OMIM RCV000000381 SCV000020525 pathogenic Neurofibromatosis, type 1 1998-08-01 no assertion criteria provided literature only

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