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

gnomAD frequency: 0.00001  dbSNP: rs1060500376

Total submissions: 9

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
Labcorp Genetics (formerly Invitae), Labcorp	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
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000660100	SCV005400600	pathogenic	Neurofibromatosis, type 1	2024-10-09	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated juvenile myelomonocytic leukemia (MIM#607785), familial spinal neurofibromatosis (MIM#162210), neurofibromatosis, type 1 (MIM#162200), neurofibromatosis-Noonan syndrome (MIM#601321) and Watson syndrome (MIM#193520). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Disease manifestation can be extremely variable, even within a family (PMID: 20301288). (I) 0209 - Splice site variant proven to affect splicing of the transcript with uncertain effect on protein sequence. Mini-gene assay using patient sample demonstrated exon 44 skipping (PMID: 9783703). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (v2+v3: 1 heterozygote, 0 homozygotes). (SP) 0311 - An alternative nucleotide change at the same canonical splice site, is present in gnomAD (v2: 1 heterozygote, 0 homozygotes). (I) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0701 - Other canonical splice variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. A total of six other changes affecting either the c.6704+1 or c.6704+2 canonical splice sites were classified as likely pathogenic/pathogenic by diagnostic laboratories in ClinVar. (SP). 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in at least three individuals with neurofibromatosis type 1, including de novo events (PMID: 9783703, 23758643, 31776437). In addition, it has been classified as pathogenic by multiple diagnostic laboratories in ClinVar. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV001257533	SCV001434359	pathogenic	Rhabdomyosarcoma	2020-09-01	no assertion criteria provided	provider interpretation