Submissions for variant NM_001042492.3(NF1):c.5609G>A (p.Arg1870Gln)

dbSNP: rs786202112

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164762	SCV000215438	pathogenic	Hereditary cancer-predisposing syndrome	2015-07-20	criteria provided, single submitter	clinical testing	The p.R1870Q pathogenic mutation (also known as c.5609G>A) is located in coding exon 38 of the NF1 gene. This pathogenic mutation results from a G to A substitution at nucleotide position 5609. The amino acid change results in an arginine to glutamine at codon 1870, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 38, which makes it likely to have some effect on normal mRNA splicing. This mutation was first described in one familial and two sporadic cases of neurofibromatosis type 1 (NF1). These researchers performed further functional studies and demonstrated a skipping of exon 38, leading to a truncated protein (Ars E, Hum. Mol. Genet. 2000 Jan; 9(2):237-47). This mutation was also identified in two unrelated individuals of Korean descent with NF1 (Ko JM, Pediatr. Neurol. 2013 Jun; 48(6):447-53) as well as in one family of Indonesian descent with NF1 (Rübben A, Mol. Cancer 2006 ; 5():36). 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 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.01% (greater than 55000 alleles tested) in our clinical cohort. Based on nucleotide sequence alignment, this position is completely conserved in available vertebrate species. Using two different splice site prediction tools, this alteration is predicted by BDGP to abolish the native donor splice site, but is predicted to weaken (but not abolish) the efficacy of the native donor splice site by ESEfinder. In the published literature, this alteration is also referred to as c.5546G>A (R1849Q). Based on the available evidence, p.R1870Q is classified as a pathogenic mutation.
Invitae	RCV000408787	SCV000542194	pathogenic	Neurofibromatosis, type 1	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1849 of the NF1 protein (p.Arg1849Gln). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with neurofibromatosis 1 (NF1) (PMID: 10607834, 10712197, 10862084, 10980545, 11857752, 12807981, 18484666, 18546366, 23668869, 23913538, 24932921, 25325900). ClinVar contains an entry for this variant (Variation ID: 185354). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in skipping of exon 37, also known as exon 29 and introduces a premature termination codon (PMID: 10607834, 10980545; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000494213	SCV000583307	pathogenic	not provided	2023-06-14	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: aberrant splicing resulting in transcripts lacking exon 37 or exons 37 and 38, also called exons 29 and 30 using alternate exon numbering (Girodon-Boulandet et al., 2000; Messiaen et al., 2000); 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; In silico analysis is inconclusive as to whether the variant alters gene splicing; This variant is associated with the following publications: (PMID: 16830335, 30014477, 10862084, 29673180, 25325900, 34418705, 23668869, 25403449, 10712197, 27322474, 19292874, 10607834, 24932921, 29489754, 28955729, 28152038, 10980545, 29618358, 31766501, 16937374, 31776437, 33372952, 33877690, 23913538)
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000408787	SCV000782055	pathogenic	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000762993	SCV000893438	pathogenic	Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis	2018-10-31	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000494213	SCV001447462	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000408787	SCV001478924	pathogenic	Neurofibromatosis, type 1	2020-10-26	criteria provided, single submitter	clinical testing
DASA	RCV000408787	SCV002061256	pathogenic	Neurofibromatosis, type 1	2022-01-05	criteria provided, single submitter	clinical testing	The c.5546G>A;p.(Arg1849Gln) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 185354; PMID: 23668869; 16937374; 10862084; 10980545; 11857752; 12807981; 10607834) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 16937374; 18546366; 10862084; 10980545) - PS3. This variant is not present in population databases (rs786202112, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Missense variant in NF1 that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease - PP2. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic.
3billion	RCV000408787	SCV002521653	pathogenic	Neurofibromatosis, type 1	2022-05-22	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Missense variant: previously reported to alter splicing and result in a loss of normal protein fucnction through nonsense-mediated decay (NMD) or protein truncation (PMID:. 10607834. Predicted Consequence/Location:). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000185354). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 10862084, 10980545, 12807981, 25325900, 29673180, 31776437). A different missense change at the same codon (p.Arg1870Leu) has been reported to be associated with NF1 related disorder (ClinVar ID: VCV001070186). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Genome-Nilou Lab	RCV000408787	SCV002560130	pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003162694	SCV003878219	pathogenic	Inborn genetic diseases	2023-02-22	criteria provided, single submitter	clinical testing	The c.5546G>A (p.R1849Q) alteration is located in coding exon 37 of the NF1 gene. This alteration results from a G to A substitution at nucleotide position 5546, causing the arginine (R) at amino acid position 1849 to be replaced by a glutamine (Q). This change occurs in the last base pair of coding exon37, which makes it likely to have some effect on normal mRNA splicing. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been detected in multiple individuals with a clinical diagnosis of neurofibromatosis type 1 (Ars, 2000; Rübben, 2006; Ko, 2013; Anastasaki, 2017; Palma Milla, 2018). This nucleotide position is highly conserved in available vertebrate species. This amino acid position is highly conserved in available vertebrate species. RNA studies have demonstrated that this variant results in skipping of coding exon 37 (Ars, 2000; Pros, 2006; Ambry internal data). In silico splice site analysis predicts that this alteration may weaken the native splice donor site. This amino acid alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Baylor Genetics	RCV003462148	SCV004199000	pathogenic	Juvenile myelomonocytic leukemia	2022-02-07	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000494213	SCV004224705	pathogenic	not provided	2023-04-26	criteria provided, single submitter	clinical testing	PM2, PS4_moderate, PVS1
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV000408787	SCV000484938	pathogenic	Neurofibromatosis, type 1		no assertion criteria provided	clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV001257532	SCV001434358	pathogenic	Rhabdomyosarcoma	2020-09-01	no assertion criteria provided	provider interpretation
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	RCV000408787	SCV003840144	pathogenic	Neurofibromatosis, type 1		no assertion criteria provided	research