Submissions for variant NM_001042492.3(NF1):c.3867C>T (p.Phe1289=)

gnomAD frequency: 0.00089  dbSNP: rs138186428

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163550	SCV000214108	likely benign	Hereditary cancer-predisposing syndrome	2014-07-24	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV000198661	SCV000252684	benign	Neurofibromatosis, type 1	2024-01-31	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000245250	SCV000306261	benign	not specified		criteria provided, single submitter	clinical testing
GeneDx	RCV000514507	SCV000521062	likely benign	not provided	2021-04-26	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 18041031, 16944272, 16199547, 15060124)
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000514507	SCV000609638	likely benign	not provided	2017-03-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000514507	SCV000696394	benign	not provided	2017-08-21	criteria provided, single submitter	clinical testing	Variant summary: The NF1 c.3867C>T (p.Phe1289Phe) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change located in the Rho GTPase activation protein domain (InterPro). One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect the binding sites for splicing enhancers. However, these predictions have yet to be confirmed by functional studies. This variant was found in the large control database ExAC in 179/121342 control chromosomes (3 homozygotes) at a frequency of 0.0014752, which is approximately 7 times the estimated maximal expected allele frequency of a pathogenic NF1 variant (0.0002084), suggesting this variant is likely a benign polymorphism. This variant was found in Neurofibromatosis type 1 patients, including in one patient co-occurring with NF-1 c.1885G>A, p.G629R (not in our internal database, DM in HGMD) and was classified as a polymorphism (Mattocks_2004, Brinckmann_2007, Griffiths_2006). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign/benign. Taken together, this variant is classified as benign.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000245250	SCV000711645	likely benign	not specified	2017-03-07	criteria provided, single submitter	clinical testing	p.Phe1289Phe in exon 28 of NF1: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 0.2% (156/66710) o f European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.br oadinstitute.org; dbSNP rs138186428).
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000198661	SCV000782004	likely benign	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000198661	SCV001287405	likely benign	Neurofibromatosis, type 1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV001128022	SCV001287406	uncertain significance	Café-au-lait macules with pulmonary stenosis	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001128023	SCV001287407	uncertain significance	Neurofibromatosis, familial spinal	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001128024	SCV001287408	uncertain significance	Neurofibromatosis-Noonan syndrome	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000514507	SCV002049585	benign	not provided	2023-10-16	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000245250	SCV002071811	likely benign	not specified	2021-02-05	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163550	SCV002527536	benign	Hereditary cancer-predisposing syndrome	2020-10-07	criteria provided, single submitter	curation
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000163550	SCV002819192	benign	Hereditary cancer-predisposing syndrome	2022-09-27	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000514507	SCV002822381	benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	NF1: BP4, BP7, BS1, BS2
Ambry Genetics	RCV003242995	SCV003941022	likely benign	Inborn genetic diseases	2023-06-01	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000198661	SCV000692351	uncertain significance	Neurofibromatosis, type 1	2016-06-03	no assertion criteria provided	clinical testing