Submissions for variant NM_001042492.3(NF1):c.3270A>C (p.Gly1090=)

gnomAD frequency: 0.00079  dbSNP: rs150015024

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163445	SCV000213992	likely benign	Hereditary cancer-predisposing syndrome	2014-11-04	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	RCV000204634	SCV000259909	benign	Neurofibromatosis, type 1	2024-02-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000252563	SCV000306254	likely benign	not specified		criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000252563	SCV000711559	benign	not specified	2014-11-24	criteria provided, single submitter	clinical testing	Gly1090Gly in exon 25 of NF1: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 1.4% (7/492) of Afri can chromosomes from a broad population by the 1000 Genomes Project (http://www. ncbi.nlm.nih.gov/projects/SNP; dbSNP rs150015024).
GeneDx	RCV000252563	SCV000726312	likely benign	not specified	2017-12-28	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000252563	SCV000919889	benign	not specified	2018-10-19	criteria provided, single submitter	clinical testing	Variant summary: NF1 c.3270A>C alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00021 in 276484 control chromosomes, predominantly at a frequency of 0.0023 within the African subpopulation in the gnomAD database. The observed variant frequency within African control individuals in the gnomAD database is approximately 11-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.3270A>C in individuals affected with Neurofibromatosis Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. Three 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/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000204634	SCV001479190	likely benign	Neurofibromatosis, type 1	2020-10-26	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000252563	SCV002068965	likely benign	not specified	2020-12-31	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163445	SCV002527499	benign	Hereditary cancer-predisposing syndrome	2020-10-27	criteria provided, single submitter	curation
Genome-Nilou Lab	RCV000204634	SCV002560651	likely benign	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315997	SCV004016443	benign	Neurofibromatosis, familial spinal	2023-07-07	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003477590	SCV004222163	uncertain significance	not provided	2012-02-03	criteria provided, single submitter	clinical testing