Submissions for variant NM_001042492.3(NF1):c.2970_2972del (p.Met992del)

dbSNP: rs267606606

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000196290	SCV000255279	pathogenic	Neurofibromatosis, type 1	2023-11-24	criteria provided, single submitter	clinical testing	This variant, c.2970_2972del, results in the deletion of 1 amino acid(s) of the NF1 protein (p.Met992del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs267606606, gnomAD no frequency). This variant has been observed in individual(s) with clinical features of NF1-related conditions (PMID: 7904209, 12807981, 17160901, 20602485, 21532985, 23047742). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 363). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000215737	SCV000273607	pathogenic	Hereditary cancer-predisposing syndrome	2015-01-19	criteria provided, single submitter	clinical testing	​The c.2970_2972delAAT pathogenic mutation (also known as p.M992del and delM992) is located in coding exon 22 of the NF1 gene. This alteration results from an in-frame AAT deletion between nucleotide positions 2970 and 2972. This results in the deletion of a highly conserved methionine residue at codon992. This alteration was first identified in two unrelated probands with paternally inherited neurofibromatosis type 1 (NF1) (Shen MH et al. Hum Mol Genet. 1993; 2(11):1861-4). Later studies suggest this mutation is associated with an attenuated form of NF1 similar to Legious syndrome; individuals with this mutation are not likely to develop neurofibromas (Upadhyaya M et al. Am J Hum Genet. 2007; 80(1):140-51). Based on the supporting evidence, c.2970_2972delAAT is interpreted as a disease-causing mutation.
GeneDx	RCV000384725	SCV000329840	pathogenic	not provided	2022-01-05	criteria provided, single submitter	clinical testing	In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26740943, 26056819, 25329635, 26345759, 12807981, 25074460, 26962827, 27920686, 28213670, 27785414, 27322453, 10712197, 10862084, 7904209, 14569132, 16380919, 16542390, 20602485, 23047742, 26457592, 25966637, 16944272, 18546366, 23656349, 25370043, 23972508, 17160901, 26178382, 24232412, 26979265, 26956402, 27838393, 30190611, 30109123, 1568246, 29968256, 31717729, 31776437, 21532985, 31370276, 32107864, 25486365, 2121369)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000196290	SCV000711759	pathogenic	Neurofibromatosis, type 1	2016-12-15	criteria provided, single submitter	clinical testing	The p.Met992del variant in NF1 has been previously reported in >20 individuals w ith NF1, segregated with disease in >20 affected relatives, and was de novo in a t least 1 of these individuals (Upadhyaya 2007, Quintans 2011). Individuals with this variant were reported to not have cutaneous neurofibromas (Upadhyaya 2007, Quintans 2011). This variant has also been reported in ClinVar (Variation ID: 3 63) and has been identified in 1/66338 European chromosomes by the Exome Aggrega tion Consortium (ExAC, http://exac.broadinstitute.org). This variant is a deleti on of 1 amino acid at position 992 and is not predicted to alter the protein rea ding frame. In summary, this variant meets our criteria to be classified as path ogenic for NF1 in an autosomal dominant manner based upon frequency in probands and segregation studies.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000196290	SCV000781967	pathogenic	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	RCV000384725	SCV000920468	pathogenic	not provided	2018-01-16	criteria provided, single submitter	clinical testing
Medical Genetics, University of Parma	RCV000196290	SCV001218919	pathogenic	Neurofibromatosis, type 1	2019-12-20	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000384725	SCV001247192	pathogenic	not provided	2017-10-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000196290	SCV001338322	pathogenic	Neurofibromatosis, type 1	2020-02-24	criteria provided, single submitter	clinical testing	Variant summary: NF1 c.2970_2972delAAT (p.Met992del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 4e-06 in 250346 control chromosomes. c.2970_2972delAAT has been reported in the literature in a large number of individuals affected with NF1 Related Conditions (e.g. Stevenson_2006, Tsipi_2018, Koczkowska_2019). These data indicate that the variant is very likely to be associated with disease. A study on 135 individuals carrying this variant showed that these individuals have a mild NF1 phenotype lacking clinically suspected plexiform, cutaneous, or subcutaneous neurofibromas (Koczkowska_2019). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000384725	SCV001447016	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000384725	SCV002018323	pathogenic	not provided	2019-11-22	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000384725	SCV002049211	pathogenic	not provided	2021-01-06	criteria provided, single submitter	clinical testing	The NF1 c.2970_2972delAAT; p.Met992del variant (rs267606606) is reported in the literature in several unrelated individuals and families affected with a milder form of neurofibromatosis type 1 (NF1), characterized by a lack of neurofibromas (Kehrer-Sawatzki 2015, Koczkowska 2019, Quintans 2011, Upadhyaya 2007). This variant is also reported in ClinVar (Variation ID: 363). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant deletes a single methionine residue leaving the rest of the protein in-frame. Based on available information, information, this variant is considered to be pathogenic. References: Kehrer-Sawatzki H et al. Neurofibromatosis Type 1 Without Neurofibromas: Genotype-Phenotype Correlations in NF1. Hum Mutat. 2015 Nov;36(11):v. Koczkowska M et al. Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype-phenotype correlation. Genet Med. 2019 Apr;21(4):867-876. Quintans B et al. Neurofibromatosis without Neurofibromas: Confirmation of a Genotype-Phenotype Correlation and Implications for Genetic Testing. Case Rep Neurol. 2011 Apr 11;3(1):86-90. Upadhyaya M et al. An absence of cutaneous neurofibromas associated with a 3-bp inframe deletion in exon 17 of the NF1 gene (c.2970-2972 delAAT): evidence of a clinically significant NF1 genotype-phenotype correlation. Am J Hum Genet. 2007 Jan;80(1):140-51.
3billion	RCV000196290	SCV002521125	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%). Inframe deletion located in a nonrepeat region: predicted to change the length of the protein and disrupt normal protein function. The variant has been previously reported as de novo in a similarly affected individual (PMID: 30190611) and observed in multiple (>3) similarly affected unrelated individuals (PMID:23656349, 30190611, 30308447). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Genome-Nilou Lab	RCV000196290	SCV002561815	pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Institute of Medical Genetics, University of Zurich	RCV000196290	SCV002569068	likely pathogenic	Neurofibromatosis, type 1	2022-05-10	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000196290	SCV002581202	pathogenic	Neurofibromatosis, type 1	2021-11-09	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002496217	SCV002809832	pathogenic	Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis	2021-09-28	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000196290	SCV004013184	pathogenic	Neurofibromatosis, type 1	2023-05-08	criteria provided, single submitter	clinical testing	PS4, PM2, PM4, PM6_Strong, PP1_Strong
Baylor Genetics	RCV003466770	SCV004199012	pathogenic	Juvenile myelomonocytic leukemia	2021-09-26	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000384725	SCV004227850	pathogenic	not provided	2022-11-23	criteria provided, single submitter	clinical testing	PP1_strong, PM2, PM6, PS4_moderate
OMIM	RCV000000392	SCV000020536	pathogenic	Neurofibromatosis-Noonan syndrome	2007-01-01	no assertion criteria provided	literature only
OMIM	RCV000000393	SCV000020537	pathogenic	Café-au-lait macules with pulmonary stenosis	2007-01-01	no assertion criteria provided	literature only
GeneReviews	RCV000196290	SCV002064274	not provided	Neurofibromatosis, type 1		no assertion provided	literature only
Laboratory for Genotyping Development, RIKEN	RCV003162200	SCV002758458	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research