Submissions for variant NM_000267.3(NF1):c.3113+1G>A (rs267606599)

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000680818	SCV000808265	pathogenic	not provided	2018-05-18	criteria provided, single submitter	clinical testing	The c.3113+1 G>A splice site variant has been previously reported in association with neurofibromatosis type 1 (Purandare et al., 1995; Emmerich et al., 2015). This variant destroys the canonical splice donor site in intron 23, and is expected to cause abnormal gene splicing. The variant is observed in 1/33570 (0.003%) alleles from individuals of Latino background in large population cohorts (Lek et al., 2016). Another splice variant at the same position, c.3113+1 G>T, has been reported in the Human Gene Mutation Database in association with neurofibromatosis type 1 (Stenson et al., 2014). In summary, we consider this variant to be pathogenic.
Invitae	RCV000000373	SCV000753640	pathogenic	Neurofibromatosis, type 1	2018-06-12	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 23 of the NF1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with neurofibromatosis, type 1 (PMID: 26962827, 18484666, 16944272, 26969325, 25293717). ClinVar contains an entry for this variant (Variation ID: 345). Experimental studies have shown that this intronic change leads to skipping of exon 23 (also called exon 18 in the literature due to legacy nomenclature of NF1 exons) at transcription (PMID: 7633431). Donor and acceptor splice site variants 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). For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000000373	SCV000020517	pathogenic	Neurofibromatosis, type 1	1995-04-01	no assertion criteria provided	literature only

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