ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.1885G>A (p.Gly629Arg) (rs199474738)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130191 SCV000185028 pathogenic Hereditary cancer-predisposing syndrome 2015-05-07 criteria provided, single submitter clinical testing <span style="font-family:arial,sans-serif; font-size:10pt">The<span style="font-family:arial,sans-serif">p.G629Rpathogenic mutation (also known as c.1885G>A), located in codingexon17 of the<span style="font-family:arial,sans-serif">NF1gene, results from a G to A substitution at nucleotide position 1885. Theglycineatcodon629 is replaced byarginine, an amino acid with dissimilar properties. This mutation has been identified in several unrelated individuals who meet diagnostic criteria forneurofibromatosistype 1 (NF1), including once as a de novo alteration in a patient with sporadic NF1 (De Luca A et al.<span style="font-family:arial,sans-serif">Hum.<span style="font-family:arial,sans-serif; font-size:10pt">Mutat<span style="font-family:arial,sans-serif; font-size:10pt">. 2004; 23:629; Mattocks C et al.<span style="font-family:arial,sans-serif">J. Med. Genet. 2004; Pros E et al.<span style="font-family:arial,sans-serif">Hum.<span style="font-family:arial,sans-serif; font-size:10pt">Mutat<span style="font-family:arial,sans-serif; font-size:10pt">. 2008; 29:E173-93; Kim MJ, et al. Korean JPediatr2014;57(9):410-5). In addition, this alteration has been shown to activate a strong alternate splice acceptor site, resulting in partialexonskipping and a translationalframeshift(41 nucleotide deletion) (Ars E et al.<span style="font-family:arial,sans-serif">J. Med. Genet. 2003; 40:e82; Pros E et al.<span style="font-family:arial,sans-serif">Hum.<span style="font-family:arial,sans-serif; font-size:10pt">Mutat<span style="font-family:arial,sans-serif; font-size:10pt">. 2008;29:E173-93;WelanderJ et al.<span style="font-family:arial,sans-serif">Hum. Mol. Genet. 2012; 21:5406-16; SabbaghA, et al. Hum.Mutat. 2013;34(11):1510-8). Based on the available evidence, p.G629R is classified as a pathogenic mutation.
Invitae RCV000206280 SCV000260849 pathogenic Neurofibromatosis, type 1 2019-12-16 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 629 of the NF1 protein (p.Gly629Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs199474738, ExAC 0.02%). This variant has been reported in the literature in multiple unrelated individuals and families affected with neurofibromatosis type 1 (PMID: 23913538, 24789688, 25324867, 12807981, 15060124, 8834249). ClinVar contains an entry for this variant (Variation ID: 68308). Experimental evidence demonstrates that this variant creates a novel acceptor splice site within the coding sequence of exon 17. This leads to the production of an mRNA that is missing the first 41 bases of exon 17 and is expected to result in a frameshift and premature stop codon (p.Gln616fs*4) (PMID: 23913538, 12807981, 18546366, 15863657). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000059160 SCV000322355 pathogenic not provided 2018-06-19 criteria provided, single submitter clinical testing The c.1885 G>A variant in the NF1 gene has been reported previously in multiple individuals with neurofibromatosis, type 1 (NF1) (Ars et al., 2003; Ko et al., 2013; Kim et al., 2014; Zhu et al., 2016; Cali et al., 2017). Although the nucleotide substitution results in the change of a Glycine to an Arginine at codon 629, the nucleotide nomenclature is used to refer to this variant since the defect is determined to be one of splicing rather than a resulting missense variant. Functional studies using cDNA/mRNA have shown that this variant creates a cryptic splice acceptor site, leading to abnormal splicing and resulting in the deletion of 41 nucleotides in exon 17 (published as exon 12) (Ars et al., 2003; Pros et al., 2008; Zhang et al., 2015). The c.1885 G>A variant is observed in 1/22,290 (0.0045%) alleles from individuals of Finnish European background in large population cohorts (Lek et al., 2016). We interpret c.1885 G>A as a pathogenic variant.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000506837 SCV000604466 pathogenic not specified 2019-05-09 criteria provided, single submitter clinical testing The NF1 c.1885G>A; p.Gly629Arg variant (rs199474738) has been reported in several unrelated individuals and families with neurofibromatosis type 1 (NF1; see link to NF1 database, Gasparini 1996, Sabbagh 2013, Zhang 2015). It is reported as pathogenic by several sources in ClinVar (Variation ID: 68308). Additionally, experimental evidences support that this missense variant leads to the creation of an acceptor splice site resulting in a transcript lacking 41 nucleotides in exon 17, leading to a frameshift in the protein (Ars 2003, Pros 2008). Based on available information, this variant is considered pathogenic. REFERENCES Link to NF1 LOVD database for p.Gly629Arg: https://grenada.lumc.nl/LOVD2/mendelian_genes/variants.php?select_db=NF1&action=search_all&search_Variant%2FDNA=c.1885G%3EA Ars E et al. (2003) Recurrent mutations in the NF1 gene are common among neurofibromatosis type 1 patients. J Med Genet. 40(6):e82. Gasparini P et al. (1996) Scanning the first part of the neurofibromatosis type 1 gene by RNA-SSCP: identification of three novel mutations and of two new polymorphisms. Hum Genet. 97(4):492-5. Pros E et al. (2008) Nature and mRNA effect of 282 different NF1 point mutations: focus on splicing alterations. Hum Mutat. 29(9):E173-93. Sabbagh A et al. (2013) NF1 molecular characterization and neurofibromatosis type I genotype-phenotype correlation: the French experience. Hum Mutat. 34(11):1510-8. Zhang J et al. (2015) Molecular Characterization of NF1 and Neurofibromatosis Type 1 Genotype-Phenotype Correlations in a Chinese Population. Sci Rep. 5:11291.
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000206280 SCV000781932 pathogenic Neurofibromatosis, type 1 2016-11-01 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000059160 SCV001144737 pathogenic not provided 2019-03-26 criteria provided, single submitter clinical testing Altered splicing results in a shift of the reading frame. Statistically enriched in patients compared to ethnically matched controls. Not found in the total gnomAD dataset, and the data is high quality (0/251196 chr). Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein.
The Laboratory of Genetics and Metabolism, Hunan Children’s Hospital RCV001009575 SCV001169676 pathogenic Neurofibromatosis, type 1; Tibial pseudoarthrosis 2018-11-10 criteria provided, single submitter research
Medical Genetics, University of Parma RCV000206280 SCV001218917 pathogenic Neurofibromatosis, type 1 2019-12-20 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000206280 SCV001366172 pathogenic Neurofibromatosis, type 1 2020-03-14 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PS4,PM2,PP4.
UniProtKB/Swiss-Prot RCV000059160 SCV000090689 not provided not provided no assertion provided not provided

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