Submissions for variant NM_001042492.3(NF1):c.6007-5A>G

dbSNP: rs267606604

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000000387	SCV000259361	pathogenic	Neurofibromatosis, type 1	2023-04-25	criteria provided, single submitter	clinical testing	Studies have shown that this variant results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 7981692, 11704931). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 359). This variant has been observed in individuals with neurofibromatosis type 1 and/or NF1-related conditions (PMID: 7981692, 10712197, 11704931, 18546366, 24789688; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 39 of the NF1 gene. It does not directly change the encoded amino acid sequence of the NF1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product.
Ambry Genetics	RCV002316183	SCV000670372	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2021-01-04	criteria provided, single submitter	clinical testing	The c.5944-5A>G intronic pathogenic mutation results from an A to G substitution 5 nucleotides upstream from coding exon 40 in the NF1 gene. This mutation has been reported in several individuals with a clinical or suspected diagnosis of neurofibromatosis type 1 (Ainsworth P et al. Hum Mol Genet, 1994 Jul;3:1179-81; Fahsold R et al. Am J Hum Genet, 2000 Mar;66:790-818; Kaufmann D et al. Am J Hum Genet, 2001 Dec;69:1395-400; Xu W et al. Int J Mol Med, 2014 Jul;34:53-60). In addition, this alteration results in the insertion of four nucleotides between NF1 exons 39 and 40, leading to creation of a premature stop codon (Ainsworth P et al. Hum Mol Genet, 1994 Jul;3:1179-81; Kaufmann D et al. Am J Hum Genet, 2001 Dec;69:1395-400; Xu W et al. Int J Mol Med, 2014 Jul;34:53-60; Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000000387	SCV000782069	pathogenic	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
Medical Genomics Laboratory, Department of Genetics UAB	RCV000000387	SCV001167431	pathogenic	Neurofibromatosis, type 1	2020-01-20	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000000387	SCV001479134	pathogenic	Neurofibromatosis, type 1	2020-10-26	criteria provided, single submitter	clinical testing
GeneDx	RCV001582455	SCV001819650	pathogenic	not provided	2020-10-22	criteria provided, single submitter	clinical testing	Non-canonical splice site variant demonstrated to result in loss-of-function (Kaufmann 2001, Pros 2008, Xu 2014, Giugliano 2019, Wimmer 2020); In silico analysis supports a deleterious effect on splicing; Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 31370276, 19221814, 24789688, 18546366, 32126153, 11704931, 10712197, 14569132, 7981692)
Genome-Nilou Lab	RCV000000387	SCV002560169	pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
OMIM	RCV000000387	SCV000020531	pathogenic	Neurofibromatosis, type 1	2001-12-01	no assertion criteria provided	literature only
OMIM	RCV000000388	SCV000020532	pathogenic	Neurofibromatosis, familial spinal	2001-12-01	no assertion criteria provided	literature only