Submissions for variant NM_001042492.3(NF1):c.5610-2A>G

dbSNP: rs1135402876

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000555506	SCV000628666	pathogenic	Neurofibromatosis, type 1	2022-12-24	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 37 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 individual(s) with neurofibromatosis (PMID: 25074460, 26969325). ClinVar contains an entry for this variant (Variation ID: 457756). 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.
MGZ Medical Genetics Center	RCV000555506	SCV002579608	pathogenic	Neurofibromatosis, type 1	2021-12-13	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002350192	SCV002649424	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2022-02-25	criteria provided, single submitter	clinical testing	The c.5547-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 38 in the NF1 gene. This mutation has been reported in multiple individuals with a clinical diagnosis of neurofibromatosis type 1 (NF1) (Pasmant E et al. Eur J Hum Genet, 2015 May;23:596-601; Ambry internal data). Another alteration impacting the same acceptor site (c.5547-1G>C) has been detected in individuals with NF1 (Ambry internal data). c.5547-2A>G is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Neuberg Centre For Genomic Medicine, NCGM	RCV000555506	SCV004100548	pathogenic	Neurofibromatosis, type 1		criteria provided, single submitter	clinical testing	The splice acceptor variant c.5547-2A>G in NF1 (NM_000267.3) has been reported previously in an affected patient (Pasmant E et al).It has been submitted to the Leiden Open Database as a de novo variant. It has been submitted to ClinVar as Likely Pathogenic. The c.5547-2A>G variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant affects an invariant splice nucleotide and hence is expected to cause protein truncation.Splice prediction tools predict a damaging effect. Loss of function variants have been decsribed previously as disease causing. For these reasons, this variant has been classified as Pathogenic.