Submissions for variant NM_001042492.3(NF1):c.4332+1G>A

dbSNP: rs1555618572

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000582123	SCV000753635	pathogenic	Neurofibromatosis, type 1	2024-04-11	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 31 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 individuals with neurofibromatosis type I (PMID: 16461335, 17311297, 28961165). ClinVar contains an entry for this variant (Variation ID: 492881). 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.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000582123	SCV001479034	pathogenic	Neurofibromatosis, type 1	2020-10-26	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000582123	SCV002560039	pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002330999	SCV002627794	likely pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2017-09-25	criteria provided, single submitter	clinical testing	The c.4269+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 31 of the NF1 gene. 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. As such, this alteration is classified as likely pathogenic.
Baylor Genetics	RCV003465317	SCV004190781	pathogenic	Juvenile myelomonocytic leukemia	2022-11-03	criteria provided, single submitter	clinical testing
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000582123	SCV000692353	pathogenic	Neurofibromatosis, type 1	2017-08-08	no assertion criteria provided	clinical testing