Submissions for variant NM_001042492.3(NF1):c.1885G>A (p.Gly629Arg)

dbSNP: rs199474738

Total submissions: 18

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	2023-12-24	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 629 of the NF1 protein (p.Gly629Arg). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with neurofibromatosis type 1 (PMID: 12807981, 18546366, 23913538; Invitae). ClinVar contains an entry for this variant (Variation ID: 68308). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NF1 protein function. Studies have shown that this missense change results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 12807981, 15863657, 18546366, 23913538; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000059160	SCV000322355	pathogenic	not provided	2021-10-25	criteria provided, single submitter	clinical testing	Exonic splice site variant demonstrated to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease (Ars 2003, Pros 2008, Sabbagh 2013, Zhang 2015, Frayling 2018); This variant is associated with the following publications: (PMID: 23668869, 12807981, 28955729, 27322474, 24803665, 28152038, 30530636, 29914388, 26962827, 8834249, 25324867, 18546366, 26056819, 27838393, 23913538, 31533797, 31730495, 31766501, 32710294, 31776437, 25486365, 29695767, 24789688, Kirat[article], 34273915)
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	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 pseudarthrosis	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.
Department of Pediatrics, Memorial Sloan Kettering Cancer Center	RCV000206280	SCV001478137	pathogenic	Neurofibromatosis, type 1	2020-12-15	criteria provided, single submitter	research
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000206280	SCV001478909	pathogenic	Neurofibromatosis, type 1	2020-10-26	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000206280	SCV002556408	pathogenic	Neurofibromatosis, type 1	2021-12-03	criteria provided, single submitter	clinical testing	The NF1 c.1885G>A variant is classified as Pathogenic (PS4_Moderate, PS3, PM2, PM6, PP3)
Genome-Nilou Lab	RCV000206280	SCV002561717	pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004549489	SCV004119942	pathogenic	NF1-related disorder	2022-08-24	criteria provided, single submitter	clinical testing	The NF1 c.1885G>A variant is predicted to result in the amino acid substitution p.Gly629Arg. This variant has been reported in multiple individuals with neurofibromatosis type 1 (see for example - Table S1 - Pros et al. 2008. PubMed ID: 18546366). Functional studies indicate this variant results in aberrant splicing resulting in a frameshift and premature protein truncation (Table S1 - Pros et al. 2008. PubMed ID: 18546366; Ars et al. 2003. PubMed ID: 12807981). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000206280	SCV004806168	uncertain significance	Neurofibromatosis, type 1	2024-03-25	criteria provided, single submitter	clinical testing
UniProtKB/Swiss-Prot	RCV000059160	SCV000090689	not provided	not provided		no assertion provided	not provided
GenomeConnect - Invitae Patient Insights Network	RCV001535533	SCV001749503	not provided	Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 01-29-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Laboratory for Genotyping Development, RIKEN	RCV003162463	SCV002758176	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research