ClinVar Miner

Submissions for variant NM_001042492.3(NF1):c.7615G>T (p.Gly2539Ter)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002393993 SCV002674062 pathogenic Hereditary cancer-predisposing syndrome; Cardiovascular phenotype 2022-09-30 criteria provided, single submitter clinical testing The p.G2518* pathogenic mutation (also known as c.7552G>T), located in coding exon 50 of the NF1 gene, results from a G to T substitution at nucleotide position 7552. This changes the amino acid from a glycine to a stop codon within coding exon 50. This change occurs in the last base pair of coding exon 50, which makes it possible to have some effect on normal mRNA splicing. This alteration was identified in an individual with a clinical diagnosis of neurofibromatosis type 1 (Heim RA et al. Hum Mol Genet, 1995 Jun;4:975-81). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp RCV003495293 SCV004296810 pathogenic Neurofibromatosis, type 1 2023-09-18 criteria provided, single submitter clinical testing This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gly2518*) in the NF1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NF1 are known to be pathogenic (PMID: 10712197, 23913538). This premature translational stop signal has been observed in individual(s) with neurofibromatosis type 1 (PMID: 7655472). ClinVar contains an entry for this variant (Variation ID: 1759493). 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.

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