Submissions for variant NM_001042492.3(NF1):c.1954C>T (p.Arg652Cys)

dbSNP: rs786202436

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165246	SCV000215961	uncertain significance	Hereditary cancer-predisposing syndrome	2014-07-30	criteria provided, single submitter	clinical testing	The p.R652C variant (also known as c.1954C>T), located in coding exon 17 of the NF1 gene, results from a C to T substitution at nucleotide position 1954. The arginine at codon 652 is replaced by cysteine, an amino acid with highly dissimilar 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 0.01% (greater than 11000 alleles tested) in our clinical cohort. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be probably damaging and tolerated by PolyPhen and SIFT in silico analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of p.R652C remains unclear.
Invitae	RCV000685531	SCV000813016	uncertain significance	Neurofibromatosis, type 1	2023-07-28	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 652 of the NF1 protein (p.Arg652Cys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 185762). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NF1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Genome-Nilou Lab	RCV000685531	SCV002561969	uncertain significance	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Pediatric/Medical Genetics, Ministry of Health, Qatif Central Hospital	RCV000685531	SCV002817377	benign	Neurofibromatosis, type 1		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003162696	SCV003897482	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2022-11-18	criteria provided, single submitter	clinical testing	The c.1954C>T (p.R652C) alteration is located in exon 17 (coding exon 17) of the NF1 gene. This alteration results from a C to T substitution at nucleotide position 1954, causing the arginine (R) at amino acid position 652 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GenomeConnect, ClinGen	RCV000685531	SCV002074817	not provided	Neurofibromatosis, type 1		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 09-21-2019 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.