Submissions for variant NM_001042492.3(NF1):c.7396A>G (p.Ile2466Val)

gnomAD frequency: 0.00001  dbSNP: rs748027595

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000200710	SCV000254511	uncertain significance	Neurofibromatosis, type 1	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2445 of the NF1 protein (p.Ile2445Val). This variant is present in population databases (rs748027595, gnomAD 0.003%). 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: 216411). 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 with a negative predictive value of 95%. 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.
Ambry Genetics	RCV002317726	SCV000666660	likely benign	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2020-09-28	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
GeneDx	RCV000681161	SCV000808619	likely benign	not provided	2020-12-09	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000764116	SCV000895084	uncertain significance	Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis	2018-10-31	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000575889	SCV002528099	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-19	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV004553095	SCV004120559	uncertain significance	NF1-related disorder	2023-07-05	criteria provided, single submitter	clinical testing	The NF1 c.7396A>G variant is predicted to result in the amino acid substitution p.Ile2466Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0026% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-29677275-A-G) and has conflicting interpretations of likely benign and uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/216411/). Additionally, a valine (Val) is present in multiple species at the p.Ile2466 residue. Although we suspect that this variant may be benign, 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	RCV003401080	SCV004122724	uncertain significance	not specified	2023-10-11	criteria provided, single submitter	clinical testing	Variant summary: NF1 c.7333A>G (p.Ile2445Val) results in a conservative amino acid change in the encoded protein sequence. Five 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 251348 control chromosomes. 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.7333A>G in individuals affected with Neurofibromatosis Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments; three submitters classified the variant as a variant of uncertain significance, while two submitters classified it as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.