Submissions for variant NM_001042492.3(NF1):c.5035A>G (p.Ile1679Val)

gnomAD frequency: 0.00195  dbSNP: rs147327414

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129642	SCV000184437	benign	Hereditary cancer-predisposing syndrome	2015-01-22	criteria provided, single submitter	clinical testing	General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance;In silico models in agreement (benign)
Invitae	RCV000168431	SCV000219128	benign	Neurofibromatosis, type 1	2024-02-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000121634	SCV000306274	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000345616	SCV000401765	likely benign	Neurofibromatosis-Noonan syndrome	2017-04-28	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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000168431	SCV000401766	likely benign	Neurofibromatosis, type 1	2017-04-28	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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000305917	SCV000401767	likely benign	Neurofibromatosis, familial spinal	2017-04-28	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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000360704	SCV000401768	likely benign	Café-au-lait macules with pulmonary stenosis	2017-04-28	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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
GeneDx	RCV000034584	SCV000519050	benign	not provided	2016-07-07	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000034584	SCV000604460	benign	not provided	2023-11-22	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000121634	SCV000711706	benign	not specified	2016-06-02	criteria provided, single submitter	clinical testing	p.Ile1679Val in exon 37 of NF1: This variant is not expected to have clinical si gnificance because it has been identified in 3.8% (435/11578) of Latino chromoso mes, including 16 homozygous individuals by the Exome Aggregation Consortium (Ex AC, http://exac.broadinstitute.org; dbSNP rs147327414).
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000168431	SCV000782040	likely benign	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000121634	SCV000919890	benign	not specified	2018-12-05	criteria provided, single submitter	clinical testing	Variant summary: The variant, NF1 c.4972A>G (p.Ile1658Val) results in a conservative amino acid change located in the CRAL-TRIO lipid binding domain of 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 0.0045 in 277174 control chromosomes, predominantly at a frequency of 0.034 within the Latino subpopulation in the gnomAD database, including 31 homozygotes. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 163.18 fold of the estimated maximal expected allele frequency for a pathogenic variant in NF1 causing Neurofibromatosis Type 1 phenotype (0.00021), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. The variant, c.4972A>G has been reported in the literature in individuals affected with Neurofibromatosis Type 1, in which a nonsense mutation was reported to co-occur in the patient (Xu _2014), providing supporting evidence for a benign role of the variant. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as as benign (5X) or likely benign (2X). Based on the evidence outlined above, the variant was classified as benign.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000168431	SCV001479292	benign	Neurofibromatosis, type 1	2020-10-26	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000121634	SCV002550899	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000168431	SCV002560796	likely benign	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002490459	SCV002803521	likely benign	Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis	2021-11-12	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034584	SCV000043390	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
ITMI	RCV000121634	SCV000085832	not provided	not specified	2013-09-19	no assertion provided	reference population