Submissions for variant NM_001042492.3(NF1):c.4174-8_4174-6del

dbSNP: rs751729752

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000203818	SCV000262342	benign	Neurofibromatosis, type 1	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000679389	SCV000568608	likely benign	not provided	2020-10-20	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 15060124)
PreventionGenetics, part of Exact Sciences	RCV000679389	SCV000806280	likely benign	not provided	2014-02-21	criteria provided, single submitter	clinical testing
Mendelics	RCV000203818	SCV000839146	likely benign	Neurofibromatosis, type 1	2018-07-02	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000679389	SCV001151261	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	NF1: BP4, BS1
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001579747	SCV002511461	benign	not specified	2022-04-19	criteria provided, single submitter	clinical testing	Variant summary: NF1 c.4111-8_4111-6delGTT alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. A mini-gene assay showed the variant to not impact splicing (Morbidoni_2021). The variant allele was found at a frequency of 0.00046 in 251202 control chromosomes, predominantly at a frequency of 0.00088 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 4.22 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 Non-Finnish European origin. c.4111-8_4111-6delGTT has been reported in the literature in individuals affected with Neurofibromatosis Type 1, and in one family the variant did not segregate with disease (Morbidoni_2021). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation: three classified as likely benign/benign while one classified as VUS. Based on the evidence outlined above, the variant was classified as benign.
Sema4, Sema4	RCV002256122	SCV002527553	likely benign	Hereditary cancer-predisposing syndrome	2021-03-30	criteria provided, single submitter	curation
Genome-Nilou Lab	RCV000203818	SCV002560714	benign	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Medical Genetics, University of Parma	RCV000203818	SCV002567752	likely benign	Neurofibromatosis, type 1	2022-08-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004558459	SCV003745298	likely benign	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2022-02-28	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.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001579747	SCV001808378	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000679389	SCV001975760	likely benign	not provided		no assertion criteria provided	clinical testing