Submissions for variant NM_001042492.3(NF1):c.1976G>A (p.Arg659Gln)

gnomAD frequency: 0.00029  dbSNP: rs151138158

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163421	SCV000213964	uncertain significance	Hereditary cancer-predisposing syndrome	2015-12-06	criteria provided, single submitter	clinical testing	The p.R659Q variant (also known as c.1976G>A), located in coding exon 17 of the NF1 gene, results from a G to A substitution at nucleotide position 1976. The arginine at codon 659 is replaced by glutamine, an amino acid with highly similar properties. This variant was previously reported in the SNPDatabase as rs151138158. Based on data from the 1000 Genomes Project, the A allele has an overall frequency of approximately 0.05% (1/2098) total alleles studied. The highest observed frequency was 0.54% (1/186) Finnish alleles. Based on data from the NHLBI Exome Sequencing Project (ESP), the A allele has an overall frequency of approximately 0.01% (1/13006) total alleles studied, having been observed in0.01% (1/8600) European American alleles. To date, this alteration has been detected with an allele frequency of approximately 0.005% (greater than 110000alleles tested) in our clinical cohort. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be possibly damaging by PolyPhen but tolerated by SIFT in silico analyses. Since supporting evidence is limited at this time, the clinical significance of p.R659Q remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000547195	SCV000628402	benign	Neurofibromatosis, type 1	2025-01-14	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825676	SCV000967095	benign	not specified	2018-04-04	criteria provided, single submitter	clinical testing	p.Arg659Gln in exon 17 of NF1: This variant is classified as benign because it h as been identified in 0.4% (106/25762) of Finnish chromosomes by the Genome Aggr egation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs151138158). ACMG/AMP Criteria applied: BA1.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000825676	SCV001478623	benign	not specified	2021-01-30	criteria provided, single submitter	clinical testing	Variant summary: NF1 c.1976G>A (p.Arg659Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00047 in 251032 control chromosomes. The observed variant frequency is approximately 2.3 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 benign. To our knowledge, no occurrence of c.1976G>A 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 (Benign, n=2). Based on the evidence outlined above, the variant was classified as benign.
Ambry Genetics	RCV002415710	SCV002719002	benign	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2021-10-06	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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.
PreventionGenetics, part of Exact Sciences	RCV004551397	SCV004723310	likely benign	NF1-related disorder	2019-04-01	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).