Submissions for variant NM_001042492.3(NF1):c.5049C>T (p.Asn1683=)

gnomAD frequency: 0.00012  dbSNP: rs140994965

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164013	SCV000214618	likely benign	Hereditary cancer-predisposing syndrome	2014-07-07	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	RCV001083508	SCV000253214	benign	Neurofibromatosis, type 1	2024-01-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000679396	SCV000527580	likely benign	not provided	2018-03-30	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.
PreventionGenetics, part of Exact Sciences	RCV000679396	SCV000806290	likely benign	not provided	2017-02-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781665	SCV000919881	benign	not specified	2018-03-28	criteria provided, single submitter	clinical testing	Variant summary: NF1 c.4986C>T alters a non-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 0.0001191 in 277132 control chromosomes (gnomAD). The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately 8-folds higher than 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 population(s) of Ashkenazi Jewish origin. To our knowledge, no occurrence of c.4986C>T in individuals affected with Neurofibromatosis Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "benign." Based on the evidence outlined above, the variant was classified as benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000781665	SCV001159841	likely benign	not specified	2019-01-15	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001126127	SCV001285285	uncertain significance	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 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	RCV001126128	SCV001285286	uncertain significance	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 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	RCV001083508	SCV001285287	uncertain significance	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). 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	RCV001126129	SCV001285288	uncertain significance	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 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.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001083508	SCV001479192	likely benign	Neurofibromatosis, type 1	2020-10-26	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000781665	SCV002071856	likely benign	not specified	2019-01-09	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000164013	SCV002527599	likely benign	Hereditary cancer-predisposing syndrome	2020-11-17	criteria provided, single submitter	curation
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000164013	SCV005205772	likely benign	Hereditary cancer-predisposing syndrome	2024-06-18	criteria provided, single submitter	clinical testing