Submissions for variant NM_001042492.3(NF1):c.3436G>A (p.Val1146Ile)

gnomAD frequency: 0.00015  dbSNP: rs201047812

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129967	SCV000184791	likely benign	Hereditary cancer-predisposing syndrome	2015-12-06	criteria provided, single submitter	clinical testing	Does not segregate with disease in family study (genes with incomplete penetrance);in silico models in agreement (benign);Other data supporting benign classification
Invitae	RCV000200527	SCV000254494	likely benign	Neurofibromatosis, type 1	2024-02-01	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000612512	SCV000711646	uncertain significance	not specified	2016-08-11	criteria provided, single submitter	clinical testing	The p.Val1164Ile variant in NF1 has been reported in 3 individuals with Neurofib romatosis type 1 (NF1; Trovo 2004, Mendelian Genes). This variant has also been identified in 11/66714 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs201047812). An additional amino a cid change at this position (p.Val1164 Phe) has been reported to occur de novo i n two individuals with NF1 (Mendelian Genes), suggesting that a change at this p osition may not be tolerated. However, valine (Val) at position 1146 is not cons erved in evolutionary distant species, with multiple fish species carrying an is oleucine (Ile) at this position, and raising the possibility that a change at th is position may be tolerated. Additional computational prediction tools suggest that the p.Val1146Ile variant may not impact the protein, though this informatio n is not predictive enough to rule out pathogenicity. In summary, due to conflic ting data, the clinical significance of the p.Val1146Ile variant is uncertain.
GeneKor MSA	RCV000129967	SCV000822095	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Mendelics	RCV000200527	SCV000839142	uncertain significance	Neurofibromatosis, type 1	2018-07-02	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001125917	SCV001285051	uncertain significance	Neurofibromatosis-Noonan syndrome	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV000200527	SCV001285052	uncertain significance	Neurofibromatosis, type 1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001125918	SCV001285053	uncertain significance	Neurofibromatosis, familial spinal	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001125919	SCV001285054	uncertain significance	Café-au-lait macules with pulmonary stenosis	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000612512	SCV001363373	uncertain significance	not specified	2019-05-23	criteria provided, single submitter	clinical testing	Variant summary: NF1 c.3436G>A (p.Val1146Ile) 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 0.00013 in 251366 control chromosomes, predominantly observed within the Latino subpopulation (at a frequency of 0.00023) and the in the European (Non-Finnish) subpopulation (at frequency of 0.00019) in the gnomAD database. The variant frequency in the Latino subpopulation is higher than expected for a pathogenic variant in NF1 causing Neurofibromatosis Type 1 (0.00023 vs 0.00021), suggesting that the variant is might be benign. In addition, the variant occurs in certain European subpopulations with even higher frequencies (e.g. in the Bulgarians (0.0015), and in Southern Europeans (0.00026)) further supporting a benign role. The c.3436G>A variant has been reported in the literature in an individual affected with Neurofibromatosis Type 1, however these publications cited the variant as a polymorphism (Trovo_2004, Trovo-Marqui_2005). Therefore these reports do not provide unequivocal conclusions about association of the variant with Neurofibromatosis Type 1. A co-occurrence with another pathogenic NF1 variant has been reported (NF1 c.3892C>T (p.Gln1298X) in an internal sample), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, four classified the variant as VUS, while one classified it as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000200527	SCV001478982	uncertain significance	Neurofibromatosis, type 1	2020-10-26	criteria provided, single submitter	clinical testing
GeneDx	RCV001594850	SCV001829342	likely benign	not provided	2020-10-30	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 31159747, 15627836, 16138229, 23656349, 31891871)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001594850	SCV002049586	uncertain significance	not provided	2021-04-06	criteria provided, single submitter	clinical testing	The NF1 c.3436G>A; p.Val1146Ile variant (rs201047812) is reported in the literature in individuals affected with neurofibromatosis type 1 or another unspecified cancer, but without clear association with disease (Trovo-Marqui 2005, Tsaousis 2019). This variant is also reported in ClinVar (Variation ID: 141451), and is found in the general population with an overall allele frequency of 0.012% (33/282760 alleles) in the Genome Aggregation Database. The valine at codon 1146 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.251). Due to limited information, the clinical significance of the p.Val1146Ile variant is uncertain at this time. References: Trovo-Marqui AB et al. High frequencies of plexiform neurofibromas, mental retardation, learning difficulties, and scoliosis in Brazilian patients with neurofibromatosis type 1. Braz J Med Biol Res. 2005 Sep;38(9):1441-7. PMID: 16138229. Tsaousis et al. Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations. BMC Cancer. 2019 Jun 3;19(1):535. PMID: 31159747
Genetic Services Laboratory, University of Chicago	RCV000612512	SCV002067551	uncertain significance	not specified	2018-10-24	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129967	SCV002527510	likely benign	Hereditary cancer-predisposing syndrome	2020-10-23	criteria provided, single submitter	curation
Medical Genetics, University of Parma	RCV000200527	SCV002567765	uncertain significance	Neurofibromatosis, type 1	2022-08-17	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000200527	SCV002579669	uncertain significance	Neurofibromatosis, type 1	2022-01-24	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001594850	SCV004222164	uncertain significance	not provided	2023-02-03	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00023 (8/35432 chromosomes in Latino/Admixed American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in patients with Neurofibromatosis, type 1 (PMIDs: 23656349 (2014) and 16138229 (2005)) and breast cancer (PMID: 33471991 (2021); LOVD3 Shared (https://databases.lovd.nl/shared/)). The variant has been reported as a somatic finding in a glioma tumor sample (PMID: 31891871 (2020)). In addition, this variant has been reported in healthy control individuals (PMID: 33471991 (2021); LOVD3 Shared (https://databases.lovd.nl/shared/)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.