Submissions for variant NM_001042492.3(NF1):c.5757G>A (p.Glu1919=)

gnomAD frequency: 0.00009  dbSNP: rs141077224

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163376	SCV000213916	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.
Invitae	RCV001083474	SCV000253218	likely benign	Neurofibromatosis, type 1	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000679401	SCV000717524	likely benign	not provided	2020-11-30	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26214590)
PreventionGenetics, part of Exact Sciences	RCV000679401	SCV000806299	likely benign	not provided	2017-08-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000611445	SCV000919880	likely benign	not specified	2018-03-23	criteria provided, single submitter	clinical testing	Variant summary: NF1 c.5694G>A alters a conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was observed with an allele frequency of 0.0001 in 276970 control chromosomes (gnomAD). The observed variant frequency within Latino control individuals in the gnomAD database is comparable to 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.5694G>A in individuals affected with Neurofibromatosis Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as "likely benign." Based on the evidence outlined above, the variant was classified as likely benign.
Illumina Laboratory Services, Illumina	RCV001122482	SCV001281199	uncertain significance	Neurofibromatosis, familial spinal	2018-01-13	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	RCV001083474	SCV001281200	uncertain significance	Neurofibromatosis, type 1	2018-01-13	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	RCV001122483	SCV001281201	benign	Neurofibromatosis-Noonan syndrome	2018-01-13	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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV001122484	SCV001281202	uncertain significance	Café-au-lait macules with pulmonary stenosis	2018-01-13	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000679401	SCV001472097	likely benign	not provided	2020-08-25	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163376	SCV002527629	likely benign	Hereditary cancer-predisposing syndrome	2021-09-17	criteria provided, single submitter	curation
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV001122482	SCV004016434	likely benign	Neurofibromatosis, familial spinal	2023-07-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000679401	SCV005093413	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	NF1: BP4
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000163376	SCV001950161	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-15	no assertion criteria provided	clinical testing