Submissions for variant NM_001042492.3(NF1):c.1810T>C (p.Leu604=)

gnomAD frequency: 0.00123  dbSNP: rs142712751

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163286	SCV000213814	likely benign	Hereditary cancer-predisposing syndrome	2014-06-24	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	RCV000197954	SCV000252675	benign	Neurofibromatosis, type 1	2025-02-04	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000222209	SCV000270617	benign	not specified	2017-10-10	criteria provided, single submitter	clinical testing	p.Leu604Leu in exon 16 of NF1: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 0.2% (143/66480) o f European chromosomes and in 0.6% (61/10146) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomAD.broadinstitute.org; dbSN P rs142712751).
Ambry Genetics	RCV002310730	SCV000273238	likely benign	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2019-05-08	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.
Illumina Laboratory Services, Illumina	RCV000197954	SCV000401713	likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Laboratory Services, Illumina	RCV000387235	SCV000401714	likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Laboratory Services, Illumina	RCV000292735	SCV000401715	likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Laboratory Services, Illumina	RCV000329254	SCV000401716	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	RCV000679376	SCV000530709	likely benign	not provided	2021-06-20	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 15060124, 16944272)
Genetic Services Laboratory, University of Chicago	RCV000222209	SCV000595969	benign	not specified	2020-01-09	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000679376	SCV000604504	benign	not provided	2022-09-12	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000222209	SCV000919887	benign	not specified	2018-09-07	criteria provided, single submitter	clinical testing	Variant summary: NF1 c.1810T>C 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 allele was found at a frequency of 0.0013 in 276866 control chromosomes, predominantly at a frequency of 0.006 within the Ashkenazi Jewish subpopulation in the gnomAD database. The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately 29 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 Ashkenazi Jewish origin. c.1810T>C has been reported in the literature in an individual affected with Neurofibromatosis Type 1 (Griffiths_2006). This report does not provide an unequivocal conclusion about association of the variant with Neurofibromatosis Type 1. Co-occurrences with other pathogenic variant(s) have been reported (NF1 c.2433_2456del22), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cites the variant as benign/likely benign (6x) and once as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.
Sema4, Sema4	RCV000163286	SCV002527419	benign	Hereditary cancer-predisposing syndrome	2020-10-07	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV000679376	SCV002545907	likely benign	not provided	2024-11-01	criteria provided, single submitter	clinical testing	NF1: BP4, BP7
Genome-Nilou Lab	RCV000197954	SCV002560946	benign	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000222209	SCV002774038	benign	not specified	2021-10-19	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002505200	SCV002808567	likely benign	Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis	2022-04-11	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000679376	SCV005212423	likely benign	not provided		criteria provided, single submitter	not provided
PreventionGenetics, part of Exact Sciences	RCV004551390	SCV000806257	benign	NF1-related disorder	2019-10-25	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000679376	SCV001740538	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000222209	SCV001974525	benign	not specified		no assertion criteria provided	clinical testing