Submissions for variant NM_001042492.3(NF1):c.288+4A>G

dbSNP: rs781459468

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000474467	SCV000542018	uncertain significance	Neurofibromatosis, type 1	2023-09-14	criteria provided, single submitter	clinical testing	This sequence change falls in intron 3 of the NF1 gene. It does not directly change the encoded amino acid sequence of the NF1 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of neurofibromatosis, type 1 (PMID: 31370276). ClinVar contains an entry for this variant (Variation ID: 404451). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
GeneDx	RCV001550211	SCV001770507	likely pathogenic	not provided	2020-10-19	criteria provided, single submitter	clinical testing	Published functional studies report this variant results in an in-frame deletion of 28 amino acids in a non-repeat region (Giugliano 2019); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 31370276)
Athena Diagnostics	RCV001550211	SCV001879391	pathogenic	not provided	2021-02-17	criteria provided, single submitter	clinical testing	Assessment of experimental evidence suggests this variant will result in the removal of a section of the protein due to abnormal RNA splicing (PMID: 31370276). This variant has been identified in at least one individual with clinical features associated with this gene. Several other splice variants at this junction are reported to be pathogenic or likely pathogenic. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org).
Medical Genetics, University of Parma	RCV000474467	SCV002567795	likely pathogenic	Neurofibromatosis, type 1	2022-08-17	criteria provided, single submitter	clinical testing
NHS Central & South Genomic Laboratory Hub	RCV000474467	SCV005393964	pathogenic	Neurofibromatosis, type 1	2024-11-11	criteria provided, single submitter	clinical testing
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	RCV004783785	SCV005397738	uncertain significance	Neurofibromatosis-Noonan syndrome	2024-06-25	criteria provided, single submitter	clinical testing	This sequence variant is a single nucleotide substitution (A>G) 4 bases downstream of the donor splice site of exon 3 of 58 in the NF1 gene. This is a previously reported variant (ClinVar 404451) that has been observed in an individual with phenotypes consistent with neurofibromatosis type 1 (PMID: 31370276). This variant is absent from the gnomAD v4.1.0 population database (0/1586428 alleles). In silico splice tools predict that this A to G base change will disrupt splicing, and the nucleotide at this position is moderately conserved across the vertebrate species examined. Studies examining the functional consequence of this variant have not been published, to our knowledge. At this time, there is insufficient evidence to determine if this variant is pathogenic or benign. Therefore, we consider this a variant of uncertain significance. ACMG Criteria: PM2, PP3