ClinVar Miner

Submissions for variant NM_001042492.3(NF1):c.2T>C (p.Met1Thr)

dbSNP: rs886041346
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000324649 SCV000329836 pathogenic not provided 2022-10-12 criteria provided, single submitter clinical testing Initiation codon variant in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31871297, 10712197)
Ambry Genetics RCV002347987 SCV001179125 pathogenic Hereditary cancer-predisposing syndrome; Cardiovascular phenotype 2024-01-16 criteria provided, single submitter clinical testing The p.M1? pathogenic mutation (also known as c.2T>C) is located in coding exon 1 of the NF1 gene and results from a T to C substitution at nucleotide position 2. This alters the methionine residue at the initiation codon (ATG). This alteration was identified in one individual from a cohort of 521 German and Turkish patients with a clinical diagnosis of neurofibromatosis type I (Fahsold R et al. Am. J. Hum. Genet., 2000 Mar;66:790-818). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae RCV001855057 SCV002238411 pathogenic Neurofibromatosis, type 1 2023-09-29 criteria provided, single submitter clinical testing This sequence change affects the initiator methionine of the NF1 mRNA. The next in-frame methionine is located at codon 68. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individuals with neurofibromatosis type 1 (PMID: 10712197, 23668869, 23913538). ClinVar contains an entry for this variant (Variation ID: 280054). For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab RCV001855057 SCV002561537 pathogenic Neurofibromatosis, type 1 2022-03-15 criteria provided, single submitter clinical testing

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