Submissions for variant NM_001042492.3(NF1):c.6428-3C>T

gnomAD frequency: 0.00004  dbSNP: rs374014162

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164785	SCV000215463	uncertain significance	Hereditary cancer-predisposing syndrome	2015-12-31	criteria provided, single submitter	clinical testing	The c.6428-3C>T intronic variant (also known as c.6365-3C>T) results from a C to T substitution 3 nucleotides upstream from coding exon 43 in the NF1 gene. This variant was previously reported in the SNPDatabase as rs374014162. Based on data from the NHLBI Exome Sequencing Project (ESP), the T allele has an overall frequency of approximately 0.02% (3/13006) total alleles studied, having been observed in 0.05% (2/4406) African American alleles and 0.01% (1/8600) European American alleles. To date, this alteration has been detected with an allele frequency of approximately 0.008% (greater than 110000 alleles tested) in our clinical cohort. Other alterations at this position (c.6365-3C>G and c.6365-3C>A) have been identified in NF1 patients and reported to result in exon-skipping (Wimmer K et al. Hum. Mutat. 2007 Jun; 28(6):599-612. Pros E et al. Hum. Mutat. 2008 Sep; 29(9):E173-93). However, based on sequence alignment, thymine is the reference nucleotide in other species, indicating that a C>T substitution may be more tolerated than other changes at the c.6428-3 position. This alteration is predicted by ESEfinder to weaken the efficacy of the native acceptor splice site, but is not predicted to have a deleterious effect on the native splice acceptor site by BDGP. Since supporting evidence is limited at this time, the clinical significance of c.6428-3C>T remains unclear.
Invitae	RCV000228132	SCV000284495	likely benign	Neurofibromatosis, type 1	2024-01-28	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000444313	SCV000511104	uncertain significance	not provided	2017-01-04	criteria provided, single submitter	clinical testing	Converted during submission to Uncertain significance.
GeneDx	RCV000444313	SCV000808479	likely benign	not provided	2021-05-25	criteria provided, single submitter	clinical testing	While in silico analysis, which includes splice predictors and evolutionary conservation, supports that this variant does not alter protein structure/function, RT-PCR analysis suggested this variant results in an out-of-frame deletion of exon 42 (previously reported as exon 34), but the data were not provided (Wimmer et al. 2007; Pros et al. 2008).; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 18546366, 17311297)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780541	SCV000917884	uncertain significance	not specified	2021-07-03	criteria provided, single submitter	clinical testing	Variant summary: NF1 c.6365-3C>T alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 6.4e-05 in 251068 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in NF1 causing Neurofibromatosis Type 1 (6.4e-05 vs 0.00021), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.6365-3C>T in individuals affected with Neurofibromatosis Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. At-least one co-occurrence with another pathogenic variant(s) have been observed at our laboratory (BRIP1 c.2010dupT, p.Glu671X), providing supporting evidence for a benign role. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000444313	SCV002049618	likely benign	not provided	2021-03-02	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000164785	SCV002527658	likely benign	Hereditary cancer-predisposing syndrome	2020-12-30	criteria provided, single submitter	curation
Ambry Genetics	RCV002362856	SCV002657394	likely benign	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2018-10-29	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000164785	SCV004014878	likely benign	Hereditary cancer-predisposing syndrome	2023-06-02	criteria provided, single submitter	clinical testing