ClinVar Miner

Submissions for variant NM_001042492.3(NF1):c.1721+542A>G

dbSNP: rs2066942173
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001346706 SCV001540930 uncertain significance Neurofibromatosis, type 1 2021-07-21 criteria provided, single submitter clinical testing In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 23913538). This variant has been observed in individual(s) with clinical features of neurofibromatosis type 1 (PMID: 23913538). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change falls in intron 15 of the NF1 gene. It does not directly change the encoded amino acid sequence of the NF1 protein.
GeneDx RCV002225828 SCV002504190 likely pathogenic not provided 2020-09-14 criteria provided, single submitter clinical testing Intronic variant demonstrated to result in aberrant splicing which is predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease (De Schepper 2008, Sabbagh 2013); Observed in multiple individuals with suspected or clinically diagnosed neurofibromatosis type 1 referred for genetic testing at GeneDx and in published literature (Sabbagh 2013); This variant is associated with the following publications: (PMID: 30840646, 17914445, 23913538)
Ambry Genetics RCV002412090 SCV002716534 likely pathogenic Hereditary cancer-predisposing syndrome; Cardiovascular phenotype 2022-05-25 criteria provided, single submitter clinical testing The c.1721+542A>G intronic variant results from an A to G substitution 542 nucleotides after coding exon 15 in the NF1 gene. The variant has been detected in multiple individuals with a clinical diagnosis or suspicion of neurofibromatosis type 1 (Sabbagh A et al. Hum Mutat, 2013 Nov;34:1510-8; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in insertion of a cryptic exon in intron 15 (Sabbagh A et al. Hum Mutat, 2013 Nov;34:1510-8; Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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