ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.6755A>G (p.Lys2252Arg) (rs1060500344)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000492274 SCV000581246 uncertain significance Hereditary cancer-predisposing syndrome 2014-07-09 criteria provided, single submitter clinical testing The p.K2273R variant (also known as c.6818A>G), located in coding exon 45 of the NF1 gene, results from an A to G substitution at nucleotide position 6818. The lysine at codon 2273 is replaced by arginine, 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.<span data-redactor="verified" style="background-color: initial;">To date, this alteration has been detected with an allele frequency of approximately 0.02% (greater than 5000 alleles tested) in our clinical cohort (includes this individual). This variant is located 2 nucleotides away from the end of exon 45 and is predicted to weaken the adjacent donor splice site efficiency, however direct evidence is unavailable.<span data-redactor="verified" style="background-color: initial;">This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive.<span data-redactor="verified" style="background-color: initial;">Since supporting evidence is limited at this time, the clinical significance of<span data-redactor="verified" style="background-color: initial;">p.K2273R<strong style="background-color: initial;"><span data-redactor="verified" style="background-color: initial;">remains unclear.
Invitae RCV000735821 SCV001591760 pathogenic Neurofibromatosis, type 1 2020-08-06 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 2252 of the NF1 protein (p.Lys2252Arg). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with neurofibromatosis type 1 (PMID: 31766501, Invitae). ClinVar contains an entry for this variant (Variation ID: 428947). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Tolerated; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 31766501). This variant disrupts the c.6755A nucleotide in the NF1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 25325900, Invitae). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics RCV000735821 SCV000863540 uncertain significance Neurofibromatosis, type 1 2018-12-10 no assertion criteria provided clinical testing The observed variant NM_001042492.2: c.6818A>G(p.Lys2273Arg) in exon-45 of NF1 gene has not been reported in the 1000 Genomes and ExAC databases. The in-silico prediction of variant is damaging by LRT and MutationTaster2.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.