ClinVar Miner

Submissions for variant NM_001042492.3(NF1):c.1810T>C (p.Leu604=) (rs142712751)

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Total submissions: 13
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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
Invitae RCV000197954 SCV000252675 benign Neurofibromatosis, type 1 2019-12-31 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare 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 RCV000216728 SCV000273238 likely benign Tumor susceptibility linked to germline BAP1 mutations 2015-01-22 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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 Clinical Services Laboratory,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 Clinical Services Laboratory,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 Clinical Services Laboratory,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 2018-04-26 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 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 2017-11-10 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000679376 SCV000806257 likely benign not provided 2014-02-20 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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.

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