Submissions for variant NM_001042492.3(NF1):c.7087A>G (p.Ile2363Val)

gnomAD frequency: 0.00001  dbSNP: rs137966859

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000167434	SCV000218290	uncertain significance	Hereditary cancer-predisposing syndrome	2015-07-16	criteria provided, single submitter	clinical testing	Thep.I2363Vvariant (also known as c.7087A>G), located in coding exon 48 of theNF1gene, results from an A to G substitution at nucleotide position 7087. The isoleucine at codon 2363 is replaced by valine, an amino acid with highly similar properties. This variant was previously reported in the SNPDatabase as rs137966859. Based on data from the 1000 Genomes Project, the G allele has an overall frequency of approximately 0.05% (1/2098) total alleles studied. The highest observed frequency was 0.54% (1/184) Southern Han Chinese alleles.This variant was not reported in the NHLBI Exome Sequencing Project (ESP) population-based cohort.To date, this alteration has been detected with an allele frequency of approximately 0.01% (greater than 55000alleles tested) in our clinical cohort.Based on proteinsequence alignment, thisamino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis.Since supporting evidence is limited at this time, the clinical significance ofp.I2363Vremains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000229493	SCV000284504	benign	Neurofibromatosis, type 1	2024-08-27	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000229493	SCV002561034	uncertain significance	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
GeneDx	RCV002510805	SCV002820863	uncertain significance	not provided	2023-01-19	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
PreventionGenetics, part of Exact Sciences	RCV004552932	SCV004118790	uncertain significance	NF1-related disorder	2022-08-24	criteria provided, single submitter	clinical testing	The NF1 c.7087A>G variant is predicted to result in the amino acid substitution p.Ile2363Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0054% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-29670051-A-G). This variant is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/187685/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003398857	SCV004122557	uncertain significance	not specified	2023-10-02	criteria provided, single submitter	clinical testing	Variant summary: NF1 c.7024A>G (p.Ile2342Val) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251378 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.7024A>G in individuals affected with Neurofibromatosis Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV004558418	SCV005048719	likely benign	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2023-04-10	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	RCV002510805	SCV005624639	uncertain significance	not provided	2023-11-13	criteria provided, single submitter	clinical testing