Submissions for variant NM_001042492.3(NF1):c.7381CTT[2] (p.Leu2463del)

dbSNP: rs786203184

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166388	SCV000217180	uncertain significance	Hereditary cancer-predisposing syndrome	2014-10-15	criteria provided, single submitter	clinical testing	The c.7387_7389delCTT variant (also known as p.L2463DEL) located in coding exon 50 of the NF1 gene. This variant results from an in-frame CTT deletion between nucleotide positions 7387 and 7389. This results in the loss of a single leucine residue at codon 2463. In one study, a review of patient reports in the literature, research mutation databases, and unpublished cases described this variant in one individual with a NF1-Noonan syndrome phenotype (<span data-redactor="verified" style="background-color: initial;">Ben-Shachar S et al. Eur. J. Hum. Genet. 2013 May; 21(5):535-9).<span data-redactor="verified" style="background-color: initial;">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 style="background-color: initial;">To date, this alteration has been detected with an allele frequency of approximately 0.02% (greater than 11000 alleles tested) in our clinical cohort. <span data-redactor="verified" style="background-color: initial;">This amino acid position is highly conserved in available higher vertebrate species.<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;">c.7387_7389delCTT<span data-redactor="verified" style="background-color: initial;">remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000632330	SCV000753507	uncertain significance	Neurofibromatosis, type 1	2023-11-08	criteria provided, single submitter	clinical testing	This variant, c.7324_7326del, results in the deletion of 1 amino acid(s) of the NF1 protein (p.Leu2442del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs760990926, gnomAD 0.05%). This variant has been observed in individual(s) with neurofibromatosis-Noonan syndrome (PMID: 23047742). This variant is also known as c.7324delCTT. ClinVar contains an entry for this variant (Variation ID: 186743). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.
GeneDx	RCV001552078	SCV001772701	likely benign	not provided	2019-07-22	criteria provided, single submitter	clinical testing	In-frame deletion of 1 amino acids in a non-repeat region; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 23047742)
Ambry Genetics	RCV002381531	SCV002669759	benign	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2022-08-31	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Revvity Omics, Revvity	RCV001552078	SCV003815863	uncertain significance	not provided	2022-03-30	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV004703438	SCV004222183	likely benign	not specified	2023-01-11	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population (http://gnomad.broadinstitute.org) is higher than would generally be expected for pathogenic variants in this gene.