Submissions for variant NM_001042492.3(NF1):c.7531G>C (p.Val2511Leu)

gnomAD frequency: 0.00189  dbSNP: rs2230850

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130554	SCV000185424	likely benign	Hereditary cancer-predisposing syndrome	2015-07-31	criteria provided, single submitter	clinical testing	In silico models in agreement (benign);Subpopulation frequency in support of benign classification
Invitae	RCV001082666	SCV000252690	benign	Neurofibromatosis, type 1	2024-02-01	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000121639	SCV000270628	likely benign	not specified	2016-03-15	criteria provided, single submitter	clinical testing	p.Val2511Leu in exon 51 of NF1: This variant is not expected to have clinical si gnificance because it has been identified in 0.6% (58/10402) of African chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org/; dbSNP rs2230850).
GeneDx	RCV000680358	SCV000529106	likely benign	not provided	2021-02-05	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24728327, 20579941)
Genetic Services Laboratory, University of Chicago	RCV000121639	SCV000595976	likely benign	not specified	2016-07-26	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000121639	SCV000919885	benign	not specified	2018-08-13	criteria provided, single submitter	clinical testing	Variant summary: NF1 c.7468G>C (p.Val2490Leu) results in a conservative amino acid change in the encoded protein sequence that is located outside of any known functional domains. Four of five in-silico tools predict a benign effect of the variant on protein function. The observed variant frequency within African control individuals in the gnomAD database is approximately 25 fold of the estimated maximal expected allele frequency for a pathogenic variant in NF1 causing Neurofibromatosis Type 1 phenotype (0.00021), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. To our knowledge, no occurrence of c.7468G>C in individuals affected with Neurofibromatosis Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. Five 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 benign (1x) or likely benign (4x). Based on the evidence outlined above, the variant was classified as benign.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001082666	SCV001478989	benign	Neurofibromatosis, type 1	2020-10-26	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000680358	SCV002009286	likely benign	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000130554	SCV002528109	benign	Hereditary cancer-predisposing syndrome	2020-09-19	criteria provided, single submitter	curation
Genome-Nilou Lab	RCV001082666	SCV002561300	benign	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002498574	SCV002805375	likely benign	Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis	2021-12-21	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000130554	SCV004228010	benign	Hereditary cancer-predisposing syndrome	2023-11-06	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003905160	SCV004724346	benign	NF1-related condition	2019-07-19	criteria provided, single submitter	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
ITMI	RCV000121639	SCV000085837	not provided	not specified	2013-09-19	no assertion provided	reference population
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000680358	SCV001742727	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000680358	SCV001799982	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000680358	SCV001964774	likely benign	not provided		no assertion criteria provided	clinical testing