Submissions for variant NM_001042492.3(NF1):c.4421C>T (p.Ala1474Val)

gnomAD frequency: 0.00001  dbSNP: rs587781553

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000467450	SCV000542226	benign	Neurofibromatosis, type 1	2025-01-20	criteria provided, single submitter	clinical testing
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000467450	SCV000782023	uncertain significance	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001753511	SCV002004974	uncertain significance	not provided	2021-07-06	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27535533, 22807134)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001778748	SCV002015059	likely benign	not specified	2021-10-25	criteria provided, single submitter	clinical testing	Variant summary: NF1 c.4358C>T (p.Ala1453Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.3e-05 in 231802 control chromosomes, predominantly at a frequency of 0.0003 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 1.4 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. To our knowledge, no occurrence of c.4358C>T in individuals affected with Neurofibromatosis Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as benign and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001778748	SCV004222172	likely benign	not specified	2024-01-19	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.
Ambry Genetics	RCV004558323	SCV005048757	likely benign	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2017-06-29	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.
Fulgent Genetics, Fulgent Genetics	RCV005016436	SCV005646759	uncertain significance	Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis	2024-03-21	criteria provided, single submitter	clinical testing