Submissions for variant NM_001042492.3(NF1):c.2325+3A>T

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Servicio Canario de Salud, Hospital Universitario Nuestra Sra. de Candelaria	RCV002306239	SCV002599128	likely pathogenic	Neurofibromatosis, type 1	2022-10-14	criteria provided, single submitter	clinical testing	The c.2325+3A>T NF1 sequence change falls in intron 19 of the NF1 gene. It does not directly change the encoded amino acid sequence of the NF1 protein, but it affects a nucleotide near the consensus splice site of the intron. This variant was absent from large population studies (gnomAD no frequency). This alteration is predicted to be deleterious by in silico splicing analysis (NNSplice, NetGene2), but this prediction has not been confirmed by functional studies. A different variant affecting this nucleotide (c.2325+3A>G) has been reported in individuals with suspected neurofibromatosis type 1 and determined to be pathogenic (PMID: 23913538). This variant has been observed in one patient with suspected neurofibromatosis type 1 in our laboratory, and has been observed to occur de novo. In summary, the c.2325+3A>T variant meets our criteria to be classified as likely pathogenic based upon its absence from controls, computational evidence of pathogenicity, de novo occurrence and specific patient´s phenotype.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002306239	SCV003299685	uncertain significance	Neurofibromatosis, type 1	2022-01-15	criteria provided, single submitter	clinical testing	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. This variant disrupts the c.2325+3A nucleotide in the NF1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 23913538; Invitae). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. 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. This variant has not been reported in the literature in individuals affected with NF1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 19 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.