Submissions for variant NM_001042492.3(NF1):c.6704+1G>T

gnomAD frequency: 0.00001  dbSNP: rs1060500376

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000660100	SCV000782081	pathogenic	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
Center of Genomic medicine, Geneva, University Hospital of Geneva	RCV000710035	SCV000840410	pathogenic	Neurofibromatosis-Noonan syndrome	2018-02-19	criteria provided, single submitter	clinical testing
Invitae	RCV000660100	SCV000943202	pathogenic	Neurofibromatosis, type 1	2023-10-28	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 43 of the NF1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with neurofibromatosis type 1 (NF1) (PMID: 9783703, 23758643, 31776437, 33372952). ClinVar contains an entry for this variant (Variation ID: 547680). Studies have shown that disruption of this splice site results in exon 44 skipping and introduces a premature termination codon (PMID: 9783703). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002352076	SCV001187688	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2019-02-04	criteria provided, single submitter	clinical testing	The c.6641+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 43 of the NF1 gene. This mutation has been reported in individuals with clinical diagnoses of neurofibromatosis type 1 (Park VM et al. J. Med. Genet. 1998 Oct;35(10):813-20; Nemethova M et al. Ann. Hum. Genet. 2013 Sep;77(5):364-79). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV001565306	SCV001788631	pathogenic	not provided	2022-07-17	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele and reported to result in skipping of exon 43 in a gene for which loss of function is a known mechanism of disease (Park et al., 1998); Also known as IVS35+1G>T; This variant is associated with the following publications: (PMID: 25525159, 9783703, 23906300, 31766501, 20686819, 23758643, 33372952, 31776437)
Genome-Nilou Lab	RCV000660100	SCV002560205	pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003459562	SCV004199013	pathogenic	Juvenile myelomonocytic leukemia	2021-09-08	criteria provided, single submitter	clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV001257533	SCV001434359	pathogenic	Rhabdomyosarcoma	2020-09-01	no assertion criteria provided	provider interpretation