Submissions for variant NM_001042492.3(NF1):c.1062+2T>C

dbSNP: rs2066510391

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001229795	SCV001402252	pathogenic	Neurofibromatosis, type 1	2024-11-26	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 9 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 individuals with neurofibromatosis type 1 (PMID: 17426081, 24413922). ClinVar contains an entry for this variant (Variation ID: 956905). 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.
Ambry Genetics	RCV002411844	SCV002713194	likely pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2021-08-30	criteria provided, single submitter	clinical testing	The c.1062+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 9 in the NF1 gene. The variant has been detected in multiple individuals with a clinical diagnosis of neurofibromatosis type 1 and reported to be de novo in one individual (Bausch B et al. J Clin Endocrinol Metab, 2007 Jul;92:2784-92; Ben-Salem S et al. Childs Nerv Syst, 2014 Jul;30:1183-9). Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneDx	RCV002462848	SCV002757434	likely pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing	Canonical splice site variant expected to result in aberrant splicing, predicted to cause in-frame loss of the adjacent exon; Not observed at significant frequency in large population cohorts (gnomAD); Deletions involving coding exons of this gene are a known mechanism of disease (HGMD); This variant is associated with the following publications: (PMID: 17426081, 24413922, 23660872, 25525159)
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV004798892	SCV005420492	likely pathogenic	Café-au-lait macules with pulmonary stenosis	2024-10-04	criteria provided, single submitter	research	PVS1,PM2