Submissions for variant NM_001042492.3(NF1):c.1062+3A>G

dbSNP: rs1057521098

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000437730	SCV000521059	likely pathogenic	not provided	2017-12-19	criteria provided, single submitter	clinical testing	The c.1062+3 A>G variant has been published previously in association with neurofibromatosis type 1 (Pros et al., 2008). The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Several in-silico splice prediction models predict that c.1062+3 A>G destroys the natural splice donor site of intron 9. Additionally, mRNA studies have suggested that the variant results in skipping of exon 9 (Pros et al., 2008); however, these studies were performed using patient mRNA, and in vitro functional studies have yet to be performed. Therefore, we consider this variant to be likely pathogenic.
Invitae	RCV000583516	SCV000948669	pathogenic	Neurofibromatosis, type 1	2023-12-22	criteria provided, single submitter	clinical testing	This sequence change falls in intron 9 of the NF1 gene. It does not directly change the encoded amino acid sequence of the NF1 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with clinical features of neurofibromatosis type 1 (PMID: 18546366; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 381606). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 9, but is expected to preserve the integrity of the reading-frame (PMID: 18546366, 32123317). For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000583516	SCV002561625	likely pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Medical Genetics, University of Parma	RCV000583516	SCV002567794	likely pathogenic	Neurofibromatosis, type 1	2022-08-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002411323	SCV002717364	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2022-09-14	criteria provided, single submitter	clinical testing	The c.1062+3A>G intronic variant results from an A to G substitution 3 nucleotides after coding exon 9 in the NF1 gene. This alteration has been detected in multiple individuals with a clinical diagnosis or suspicion of neurofibromatosis type 1 (Pros E et al. Hum Mutat, 2008 Sep;29:E173-93; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in skipping of exon 9 (Pros E et al. Hum Mutat, 2008 Sep;29:E173-93; Wai HA et al. Genet Med, 2020 06;22:1005-1014; Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000583516	SCV002819462	likely pathogenic	Neurofibromatosis, type 1	2022-12-12	criteria provided, single submitter	clinical testing	Variant summary: NF1 c.1062+3A>G alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: One predict the variant abolishes a 5 prime splicing donor site; two predict the variant weakens a 5 prime donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Pros_2018, Wai_2020). The variant allele was found at a frequency of 3.8e-06 in 265890 control chromosomes. c.1062+3A>G has been reported in the literature in at least one individual with diagnosis or clinical suspicion of neurofibromatosis type 1. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (pathogenic n=2, likely pathogenic n=3, VUS n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV003470382	SCV004199029	likely pathogenic	Juvenile myelomonocytic leukemia	2021-02-10	criteria provided, single submitter	clinical testing
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000583516	SCV000692340	uncertain significance	Neurofibromatosis, type 1	2016-06-03	no assertion criteria provided	clinical testing