Submissions for variant NM_001042492.3(NF1):c.1260+1G>T

dbSNP: rs267606603

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000691582	SCV000819368	pathogenic	Neurofibromatosis, type 1	2020-08-09	criteria provided, single submitter	clinical testing	Donor and acceptor splice site variants 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). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Disruption of this splice site has been observed in individual(s) with neurofibromatosis type 1 (PMID: 10677298, Invitae). ClinVar contains an entry for this variant (Variation ID: 570670). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 11 of the NF1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.
Ambry Genetics	RCV002424625	SCV002679238	likely pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2018-08-10	criteria provided, single submitter	clinical testing	The c.1260+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 11 of 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.
GeneDx	RCV004588115	SCV005080561	pathogenic	not provided	2023-06-06	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Deletions involving coding exons of this gene are a known mechanism of disease (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10677298, 30531922)