Submissions for variant NM_001042492.3(NF1):c.6782A>G (p.His2261Arg)

dbSNP: rs201336602

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000221666	SCV000274376	uncertain significance	Hereditary cancer-predisposing syndrome	2015-03-10	criteria provided, single submitter	clinical testing	The p.H2261R variant (also known as c.6782A>G), located in coding exon 45 of the NF1 gene, results from an A to G substitution at nucleotide position 6782. The histidine at codon 2261 is replaced by arginine, an amino acid with highly similar properties. This variant was previously reported in the SNPDatabase as rs201336602, but was absent from population-based cohorts in the NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project databases. 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.H2261R remains unclear.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000034586	SCV000510829	uncertain significance	not provided	2016-10-12	criteria provided, single submitter	clinical testing	Converted during submission to Uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001212035	SCV001383607	uncertain significance	Neurofibromatosis, type 1	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 2240 of the NF1 protein (p.His2240Arg). This variant is present in population databases (rs201336602, gnomAD 0.0009%). 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: 41674). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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	RCV001212035	SCV002560997	uncertain significance	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004558287	SCV005048334	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2021-04-01	criteria provided, single submitter	clinical testing	The c.6719A>G (p.H2240R) alteration is located in exon 44 (coding exon 44) of the NF1 gene. This alteration results from a A to G substitution at nucleotide position 6719, causing the histidine (H) at amino acid position 2240 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Baylor Genetics	RCV004566800	SCV005052213	uncertain significance	Juvenile myelomonocytic leukemia	2024-02-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000034586	SCV005385182	uncertain significance	not provided	2024-01-02	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 22703879)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000034586	SCV005624634	uncertain significance	not provided	2023-12-27	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034586	SCV000043391	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.