Submissions for variant NM_001042492.3(NF1):c.6705-3C>G

dbSNP: rs1131691079

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000492195	SCV000581260	likely pathogenic	Hereditary cancer-predisposing syndrome	2014-12-08	criteria provided, single submitter	clinical testing	<span style="font-family:arial,helvetica,sans-serif"><span style="font-size:12px">Thec.6705-3C>Gintronic variant results from a C to G substitution 3 nucleotides upstream from coding exon 45 in theNF1gene. This variant was seen in one individual from the French NF1 Databasewho fulfilled NIH NF1 diagnostic criteria (Pasmant E, et al.Eur. J. Hum. Genet. 2014,14(7);10.1038).This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position.To date, this alteration has been detected with an allele frequency of approximately 0.01% (greater than11000alleles tested) in our clinical cohort.This nucleotide position is conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native acceptor splice site; however, direct evidence is unavailable.Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000817999	SCV000958587	pathogenic	Neurofibromatosis, type 1	2023-09-11	criteria provided, single submitter	clinical testing	This variant disrupts the c.6642-3C nucleotide in the NF1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 32126153). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. This sequence change falls in intron 43 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 neurofibromatosis type I (PMID: 25074460, 31730495). ClinVar contains an entry for this variant (Variation ID: 428955). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with altered splicing resulting in unknown protein product impact (PMID: 32126153). For these reasons, this variant has been classified as Pathogenic.
UAB Medical Genomics Laboratory, UAB Medicine	RCV000817999	SCV001167444	pathogenic	Neurofibromatosis, type 1	2020-01-20	criteria provided, single submitter	clinical testing
GeneDx	RCV004701557	SCV005202060	likely pathogenic	not provided	2023-12-26	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: aberrant splicing expected to lead to out-of-frame transcripts (PMID: 32126153); In silico analysis supports a deleterious effect on splicing; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: Chen2021[article], 31730495, 25074460, 32126153)