Submissions for variant NM_001042492.3(NF1):c.1756_1759del (p.Thr586fs)

dbSNP: rs786202782

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165769	SCV000216514	pathogenic	Hereditary cancer-predisposing syndrome	2015-11-12	criteria provided, single submitter	clinical testing	Thec.1756_1759delACTApathogenic mutation, located in codingexon16 of theNF1gene, results from a deletion of 4 nucleotides between nucleotide positions 1756 and 1759, causing a translational frameshift with a predicted alternate stop codon. This mutation has been reported in multiple individuals diagnosed with NF1, both sporadic and familial (Yap P et al. PediatrBlood Cancer. 2015 Oct; [epub ahead of print]; Wimmer K et al. HumMutat. 2007 Jun;28(6):599-612; Ars E et al. J Med Genet. 2003 Jun;40(6):e82; Park VM et al. J Med Genet. 1998 Oct;35(10):813-20). In one functional study, this mutation was reported in a 26 year old female with a clinical diagnosis of NF1, who was found to have 20% neurofibromin expression in fibroblasts (Anastasaki C et al. Hum. Mol. Genet. 2015 Jun; 24(12):3518-28). In addition to the clinical data presented in the literature, sinceframeshiftsare typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294).
Invitae	RCV000467300	SCV000541963	pathogenic	Neurofibromatosis, type 1	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr586Valfs*18) in the NF1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NF1 are known to be pathogenic (PMID: 10712197, 23913538). This variant is present in population databases (rs786202782, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with neurofibromatosis type 1 (PMID: 9783703, 16835897, 17311297, 18546366, 25788518). ClinVar contains an entry for this variant (Variation ID: 186215). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000484704	SCV000568603	pathogenic	not provided	2021-11-22	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect: variant results in reduced neurofibromin expression and increased RAS activity compared to wild type (Park 1998, Anatasaki 2015); This variant is associated with the following publications: (PMID: 17311297, 9783703, 26514327, 29618358, 28955729, 12807981, 16835897, 18546366, 23906300, 25788518, 28068329, 23758643, 31766501, 31533651, 31476437, 31717729, 32056211, 29625052, 32533764, 31776437)
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000467300	SCV000588376	pathogenic	Neurofibromatosis, type 1	2017-06-18	criteria provided, single submitter	clinical testing
Medical Genetics, University of Parma	RCV000467300	SCV000588734	pathogenic	Neurofibromatosis, type 1	2019-12-20	criteria provided, single submitter	clinical testing
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000467300	SCV000781929	pathogenic	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000484704	SCV000842883	pathogenic	not provided	2017-12-29	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000467300	SCV001369089	pathogenic	Neurofibromatosis, type 1	2019-05-31	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PS3,PP4.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000467300	SCV001479114	pathogenic	Neurofibromatosis, type 1	2020-10-26	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000484704	SCV001746522	pathogenic	not provided	2021-04-01	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000484704	SCV002051622	pathogenic	not provided	2021-03-08	criteria provided, single submitter	clinical testing	PVS1, PS4, PM2_Supporting, PM6
Institute of Human Genetics, University of Leipzig Medical Center	RCV000467300	SCV002505544	pathogenic	Neurofibromatosis, type 1	2023-11-21	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PS3,PS4_MOD,PM2_SUP
3billion	RCV000467300	SCV002521830	pathogenic	Neurofibromatosis, type 1	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000186215). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Genome-Nilou Lab	RCV000467300	SCV002561706	pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003162704	SCV003877630	pathogenic	Inborn genetic diseases	2023-02-10	criteria provided, single submitter	clinical testing	The c.1756_1759delACTA (p.T586Vfs*18) alteration, located in exon 16 (coding exon 16) of the NF1 gene, consists of a deletion of 4 nucleotides from position 1756 to 1759, causing a translational frameshift with a predicted alternate stop codon after 18 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported in multiple individuals diagnosed with NF1, both sporadic and familial (Park, 1998; Fahsold, 2000; Ars, 2003; H&uuml;ffmeier, 2006; Wimmer, 2007; Yap, 2016; Anastasaki, 2017; Melloni, 2019; Yao, 2019; Kang, 2020; Peces, 2020; N Abdel-Aziz, 2021; Riva, 2022). Based on the available evidence, this alteration is classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004552913	SCV004120036	pathogenic	NF1-related disorder	2023-04-19	criteria provided, single submitter	clinical testing	The NF1 c.1756_1759delACTA variant is predicted to result in a frameshift and premature protein termination (p.Thr586Valfs*18). This variant was reported in individuals with Neurofibromatosis 1 (see for example - Park et al. 1998. PubMed ID: 9783703; Anastasaki et al. 2015. PubMed ID: 25788518; Corsello et al. 2018. PubMed ID: 29618358). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-29550493-TTAAC-T) and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/186215/). Frameshift variants in NF1 are expected to be pathogenic. This variant is interpreted as pathogenic.
Baylor Genetics	RCV003468755	SCV004190711	pathogenic	Juvenile myelomonocytic leukemia	2023-05-25	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000484704	SCV004222157	pathogenic	not provided	2017-12-29	criteria provided, single submitter	clinical testing	This frameshift variant alters the translational reading frame of the NF1 mRNA and causes the premature termination of NF1 protein synthesis. The frequency of this variant in the general population, 0.000004 (1/251120 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with neurofibromatosis 1 (PMID: 31776437 (2020), 32533764 (2020), 34080803 (2021), 34080803 (2022)). A functional study found this variant results in reduced neurofibromin expression compared to wild type (PMID: 25788518 (2015)). Based on the available information, this variant is classified as pathogenic.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000467300	SCV004807998	uncertain significance	Neurofibromatosis, type 1	2024-03-29	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000467300	SCV005045617	pathogenic	Neurofibromatosis, type 1	2024-05-28	criteria provided, single submitter	clinical testing
Department of Ophthalmology, Shanghai Ninth people hospital, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University	RCV000787330	SCV000926272	pathogenic	Neurofibroma	2019-06-29	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000484704	SCV001979764	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000484704	SCV001979981	pathogenic	not provided		no assertion criteria provided	clinical testing