Submissions for variant NM_001042492.3(NF1):c.4749A>G (p.Glu1583=)

gnomAD frequency: 0.00019  dbSNP: rs144091165

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163873	SCV000214460	likely benign	Hereditary cancer-predisposing syndrome	2014-10-09	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000206001	SCV000260928	likely benign	Neurofibromatosis, type 1	2025-01-29	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000269925	SCV000401749	uncertain significance	Neurofibromatosis, familial spinal	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000206001	SCV000401750	uncertain significance	Neurofibromatosis, type 1	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000360964	SCV000401751	uncertain significance	Café-au-lait macules with pulmonary stenosis	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000266821	SCV000401752	likely benign	Neurofibromatosis-Noonan syndrome	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
GeneDx	RCV000679394	SCV000721499	likely benign	not provided	2021-10-26	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 21354044)
PreventionGenetics, part of Exact Sciences	RCV000679394	SCV000806285	likely benign	not provided	2017-10-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000604815	SCV001362230	benign	not specified	2019-12-07	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000604815	SCV002071845	likely benign	not specified	2017-08-23	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163873	SCV002527583	likely benign	Hereditary cancer-predisposing syndrome	2021-03-01	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV000679394	SCV004033550	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	NF1: BP4, BP7
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000163873	SCV005688892	benign	Hereditary cancer-predisposing syndrome	2024-11-20	criteria provided, single submitter	clinical testing	The synonymous variant NM_000267.3(NF1):c.4686A>G (p.Glu1562=) has not been reported previously as a pathogenic variant, to our knowledge. The variant is observed in one or more well-documented healthy adults. The p.Glu1562= variant is not predicted to disrupt an existing splice site. The p.Glu1562= variant results in a substitution of a base that is not predicted conserved by GERP++ and PhyloP. For these reasons, this variant has been classified as Likely Benign.