Submissions for variant NM_001042492.3(NF1):c.6393C>T (p.His2131=)

gnomAD frequency: 0.00655  dbSNP: rs17881788

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163437	SCV000213984	benign	Hereditary cancer-predisposing syndrome	2014-07-28	criteria provided, single submitter	clinical testing	General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
Labcorp Genetics (formerly Invitae), Labcorp	RCV000203810	SCV000262141	benign	Neurofibromatosis, type 1	2025-02-04	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000250079	SCV000306282	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000203810	SCV000401769	benign	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 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	RCV000302524	SCV000401770	benign	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 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	RCV000357379	SCV000401771	benign	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 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	RCV000262874	SCV000401772	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.
GeneDx	RCV000586790	SCV000518955	benign	not provided	2016-09-20	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.
Genetic Services Laboratory, University of Chicago	RCV000250079	SCV000595974	benign	not specified	2016-11-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586790	SCV000696402	benign	not provided	2017-07-06	criteria provided, single submitter	clinical testing	Variant summary: The NF1 c.6330C>T (p.His2110His) variant involves the alteration of a conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant of interest has been found in a large, broad control population, ExAC in 228/121380 control chromosomes at a frequency of 0.0018784, which is approximately 9 times the estimated maximal expected allele frequency of a pathogenic NF1 variant (0.0002084), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000250079	SCV000711562	benign	not specified	2014-11-24	criteria provided, single submitter	clinical testing	His2131His in exon 42 of NF1: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 2.0% (89/4406) of Af rican American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs17881788).
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000586790	SCV000884233	benign	not provided	2017-06-07	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000203810	SCV001478994	benign	Neurofibromatosis, type 1	2020-10-26	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000203810	SCV002561215	benign	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000357379	SCV004016451	benign	Neurofibromatosis, familial spinal	2023-07-07	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000586790	SCV005253793	benign	not provided		criteria provided, single submitter	not provided
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000250079	SCV001809139	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000250079	SCV001973140	benign	not specified		no assertion criteria provided	clinical testing