Submissions for variant NM_001042492.3(NF1):c.1845+2T>G

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV002306187	SCV002599945	pathogenic	not provided	2022-05-06	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele 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: 29625052, 31573083)
Ambry Genetics	RCV002409652	SCV002715820	likely pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2017-02-27	criteria provided, single submitter	clinical testing	The c.1845+2T>G intronic variant results from a T to G substitution two nucleotides after coding exon 16 in the NF1 gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. 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 likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003099099	SCV003284843	pathogenic	Neurofibromatosis, type 1	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 16 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 individual(s) with NF1-related conditions (PMID: 29625052, 31573083). ClinVar contains an entry for this variant (Variation ID: 1723080). 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.
NHS Central & South Genomic Laboratory Hub	RCV003099099	SCV005393958	pathogenic	Neurofibromatosis, type 1	2024-11-11	criteria provided, single submitter	clinical testing