ClinVar Miner

Submissions for variant NM_001042492.3(NF1):c.6642+1G>T

dbSNP: rs1060500345
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000458814 SCV000542156 pathogenic Neurofibromatosis, type 1 2023-10-14 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 42 of the NF1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in NF1 are known to be pathogenic (PMID: 10712197, 23913538). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with clinical features of neurofibromatosis type 1 (PMID: 16835897, 23913538; Invitae). ClinVar contains an entry for this variant (Variation ID: 404558). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Center for Human Genetics, Inc, Center for Human Genetics, Inc RCV000458814 SCV000782076 pathogenic Neurofibromatosis, type 1 2016-11-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV002356636 SCV001187613 pathogenic Hereditary cancer-predisposing syndrome; Cardiovascular phenotype 2020-06-01 criteria provided, single submitter clinical testing The c.6579+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 42 of the NF1 gene. This alteration was reported in two individuals with a clinical diagnosis of neurofibromatosis type 1 (Sabbagh A et al. Hum. Mutat., 2013 Nov;34:1510-8). In addition, this alteration was identified in a child under age 10 with at least six cafe-au-lait macules, freckling, and neurofibromas (Giugliano T et al. Genes (Basel), 2019 07;10). RNA data indicate that this variant affects the donor site and results in an out-of-frame transcript (Giugliano T et al. Genes (Basel), 2019 07;10; Sabbagh A et al. Hum. Mutat., 2013 Nov;34:1510-8). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Medical Genetics, University of Parma RCV000458814 SCV001218925 pathogenic Neurofibromatosis, type 1 2019-12-20 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000458814 SCV002560196 pathogenic Neurofibromatosis, type 1 2022-03-15 criteria provided, single submitter clinical testing
GeneDx RCV004701487 SCV005202059 pathogenic not provided 2024-01-31 criteria provided, single submitter clinical testing Canonical splice site variant demonstrated to result in exon skipping in a gene for which loss of function is a known mechanism of disease (PMID: 31370276); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23913538, 34427956, 31370276)

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