Submissions for variant NM_001042492.3(NF1):c.7910G>A (p.Arg2637Gln)

gnomAD frequency: 0.00003  dbSNP: rs560262404

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129502	SCV000184274	uncertain significance	Hereditary cancer-predisposing syndrome	2015-11-06	criteria provided, single submitter	clinical testing	Thep.R2637Qvariant (also known as c.7910G>A), located in coding exon 54 of theNF1gene, results from a G to A substitution at nucleotide position 7910. The arginine at codon 2637 is replaced by glutamine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.004% (greater than 110000 alleles tested) in our clinical cohort. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of p.R2637Q remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000458322	SCV000554962	likely benign	Neurofibromatosis, type 1	2024-01-25	criteria provided, single submitter	clinical testing
Phosphorus, Inc.	RCV000458322	SCV000679830	uncertain significance	Neurofibromatosis, type 1	2017-08-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000679416	SCV000808670	uncertain significance	not provided	2018-04-18	criteria provided, single submitter	clinical testing	This variant is denoted NF1 c.7847G>A at the cDNA level, p.Arg2616Gln (R2616Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGA>CAA). This variant was observed in a family with a clinical diagnosis of neurofibromatosis type 1; however, a pathogenic nonsense variant in NF1 was found to segregate with disease in this family (Messiaen 2000). This variant was also observed in two siblings with Asperger syndrome (Toma 2014). NF1 Arg2616Gln was observed at an allele frequency of 0.007% (8/111,574) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is located in the C-terminal domain (Luo 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether NF1 Arg2616Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000679416	SCV000884247	likely benign	not provided	2017-06-16	criteria provided, single submitter	clinical testing	The NF1 c.7910G>A; p.Arg2637Gln variant (rs560262404), also known as c.7847G>A; p.Arg2616Gln, has been reported in the literature in a patient who carries a pathogenic NF1 variant in trans, and did not segregate with disease in this family (Messiaen 2000). This variant is reported in ClinVar (Variation ID: 141130), and is observed in general population databases at frequencies of 0.02 percent (1/5008 alleles, 1000 Genome Project), and 0.007 percent (8/111574 alleles, Genome Aggregation Database). The arginine at codon 2637 is highly conserved, but computational algorithms do not agree as to the effect this variant may have on the protein (SIFT: Tolerated, PolyPhen2: Probably Damaging, MutationTaster: Disease Causing, Align GVGD: C0). Taken together, this variant is considered likely benign. REFERENCES Link to ClinVar database for p.Arg2637Gln: https://www.ncbi.nlm.nih.gov/clinvar/variation/141130/ Messiaen LM et al. Exhaustive mutation analysis of the NF1 gene allows identification of 95% of mutations and reveals a high frequency of unusual splicing defects. Hum Mutat. 2000;15(6):541-55.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000458322	SCV002526098	uncertain significance	Neurofibromatosis, type 1	2022-03-10	criteria provided, single submitter	clinical testing	The NF1 c.7847G>A (p.Arg2616Gln) missense change has a maximum subpopulation frequency of 0.0070% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/17-29684327-G-A?dataset=gnomad_r2_1 ). In silico tools are not in agreement about the effect of this variant on protein function, but to our knowledge these predictions have not been confirmed by functional assays. In one family with neurofibromatosis type 1, this variant was found to co-occur with a pathogenic NF1 mutation p.Arg304* in the proband, but did not co-segregate with disease in one affected family member (BP2; PMID: 10862084). This variant was also reported in an individual with VGLL2-rearranged rhabdomyosarcoma (PMID: 339493441), and in two siblings with Asperger syndrome (PMID: 23999528). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BP2.
Medical Genetics, University of Parma	RCV000458322	SCV002567769	uncertain significance	Neurofibromatosis, type 1	2022-08-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002408637	SCV002670052	likely benign	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2019-03-28	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000679416	SCV002774825	uncertain significance	not provided	2021-08-05	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004737219	SCV000806322	likely benign	NF1-related disorder	2024-03-05	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).