Submissions for variant NM_001042492.3(NF1):c.574C>T (p.Arg192Ter)

gnomAD frequency: 0.00001  dbSNP: rs397514641

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000033171	SCV000218634	pathogenic	Neurofibromatosis, type 1	2023-12-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg192*) 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 (rs397514641, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with neurofibromatosis type 1 (PMID: 10712197, 10726756, 15146469, 16835897, 21278392, 26056819, 27838393). ClinVar contains an entry for this variant (Variation ID: 40093). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000442381	SCV000521057	pathogenic	not provided	2022-03-28	criteria provided, single submitter	clinical testing	Nonsense 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; This variant is associated with the following publications: (PMID: 10726756, 15846561, 19142971, 17353900, 17406642, 10712197, 10862084, 12095621, 15146469, 27625798, 25525159, 26056819, 27838393, 28529006, 31347283, 31717729, 30613976, 32581362, 31370276, 31776437)
Ambry Genetics	RCV002310996	SCV000581337	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2022-04-18	criteria provided, single submitter	clinical testing	The p.R192* pathogenic mutation (also known as c.574C>T), located in coding exon 5 of the NF1 gene, results from a C to T substitution at nucleotide position 574. This changes the amino acid from an arginine to a stop codon within coding exon 5. This mutation has been identified in numerous individuals who meet clinical criteria for neurofibromatosis type 1 (NF1) (Toliat MR et al. Electrophoresis. 2000 Feb;21:541-4; Fahsold R et al. Am. J. Hum. Genet. 2000 Mar;66:790-818; De Luca A et al. Hum. Mutat. 2004 Jun;23:629; Lee MJ et al. Hum. Mutat. 2006 Aug;27:832; Cali F et. al Eur J Med Genet. 2017 Feb;60(2):93-99; Wu-Chou YH et al. J. Biomed. Sci. 2018 Oct;25(1):72). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Medical Genetics, University of Parma	RCV000033171	SCV000588698	pathogenic	Neurofibromatosis, type 1	2019-12-20	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000626737	SCV000747440	pathogenic	Cafe au lait spots, multiple; Axillary freckling; Focal T2 hyperintense basal ganglia lesion	2017-01-01	criteria provided, single submitter	clinical testing
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000033171	SCV000781874	pathogenic	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000442381	SCV000842893	pathogenic	not provided	2021-04-19	criteria provided, single submitter	clinical testing	This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene.
Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn	RCV000033171	SCV000999356	pathogenic	Neurofibromatosis, type 1		criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000033171	SCV001479214	pathogenic	Neurofibromatosis, type 1	2020-10-26	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000442381	SCV001746520	pathogenic	not provided	2021-02-01	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000033171	SCV002061777	pathogenic	Neurofibromatosis, type 1	2021-12-09	criteria provided, single submitter	clinical testing	PVS1, PS4, PP1, PM2_Supporting, PM6
Genome-Nilou Lab	RCV000033171	SCV002561585	pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Institute of Medical Genetics, University of Zurich	RCV000033171	SCV002569050	pathogenic	Neurofibromatosis, type 1	2022-05-15	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000033171	SCV002581880	pathogenic	Neurofibromatosis, type 1	2022-09-06	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000033171	SCV002768237	pathogenic	Neurofibromatosis, type 1	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with neurofibromatosis type 1 (MIM#162200). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity (GeneReviews). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar, DECIPHER). (SP) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple individuals with neurofibromatosis type 1 (PMID: 27838393). (SP) 1205 - This variant has been shown to be maternally inherited (by segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000442381	SCV002774392	pathogenic	not provided	2021-04-19	criteria provided, single submitter	clinical testing	The NF1 c.574C>T (p.Arg192*) variant causes the premature termination of NF1 protein synthesis. This variant has been reported in the published literature in multiple individuals and families with NF1 in the published literature (PMID: 27838393 (2017), 26056819 (2015), 21278392 (2011), 19142971 (2009), 17406642 (2007), 16835897 (2006), 15146469 (2004), 10862084 (2000), 10726756 (2000), 10712197 (2000)). The frequency of this variant in the general population, 0.000004 (1/250636 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
Institute of Human Genetics, University Hospital Muenster	RCV003231110	SCV003929499	pathogenic	See cases	2023-03-01	criteria provided, single submitter	clinical testing	ACMG categories: PVS1,PM1,PP5
Baylor Genetics	RCV003460540	SCV004190785	pathogenic	Juvenile myelomonocytic leukemia	2023-12-07	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000033171	SCV005382518	pathogenic	Neurofibromatosis, type 1	2023-05-20	criteria provided, single submitter	clinical testing	The stop gained c.574C>T (p.Arg192Ter) variant in the NF1 gene has been reported previously in has been observed in individual(s) with neurofibromatosis type 1 (Toliat, M R et al.,2000). This variant is reported with the allele frequency (0.0003%) in the gnomAD Exome. It is submitted to ClinVar as Pathogenic (multiple submissions). Computational evidence (MutationTaster - Disease causing) predicts damaging effect on protein structure and function for this variant. This variant is predicted to cause loss of normal protein function through protein truncation. The nucleotide change c.574C>T in NF1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000033171	SCV000056953	pathogenic	Neurofibromatosis, type 1	2007-08-01	no assertion criteria provided	literature only
NIHR Bioresource Rare Diseases, University of Cambridge	RCV001003806	SCV001162255	likely pathogenic	Juvenile myelomonocytic leukemia; Neurofibroma		no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000442381	SCV001963067	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000442381	SCV001970884	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)	RCV000033171	SCV003927940	pathogenic	Neurofibromatosis, type 1	2023-04-01	no assertion criteria provided	clinical testing