Submissions for variant NM_001042492.3(NF1):c.204+3_204+6del

dbSNP: rs1567814632

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000702165	SCV000831006	pathogenic	Neurofibromatosis, type 1	2023-07-19	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ser47 amino acid residue in NF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27322474, 27716896). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in the activation of a cryptic splice site in exon 2 (PMID: 27322474, 31868168). ClinVar contains an entry for this variant (Variation ID: 578995). This variant has been observed in individual(s) with neurofibromatosis, type 1 (PMID: 27322474, 31868168). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 2 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 likely results in the loss of 35 amino acid residue(s), but is expected to preserve the integrity of the reading-frame.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000702165	SCV001479081	likely pathogenic	Neurofibromatosis, type 1	2024-07-16	criteria provided, single submitter	clinical testing	This variant results in a deletion of 4 nucleotides in intron 2 of the NF1 gene. It has been reported previously in individuals with Neurofibromatosis type 1 (PMIDs: 27322474; 31868168). In silico prediction programs predict that this variant may affect splicing, and RNA functional analysis indicates that this variant results in abberrant splicing (PMID: 27322474). This variant has not been observed in population controls of the Genome Aggregation Database (gnomAD). Based on the evidence above, this variant is classified as likely pathogenic (ACMG criteria - PS4_Moderate, PM2, PP3, PP5)
Ambry Genetics	RCV002422577	SCV002718780	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2022-01-10	criteria provided, single submitter	clinical testing	The c.204+3_204+6delGAGT intronic pathogenic mutation, located in intron 2 of the NF1 gene, results from a deletion of 4 nucleotides within intron 2 of the NF1 gene. This alteration has been reported in an individual meeting NIH diagnostic criteria for Neurofibromatosis type 1 (NF1)(Evans DG et al. EBioMedicine, 2016 May;7:212-20). In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing that result in partial deletion of a coding exon 2 (Evans DG et al. EBioMedicine, 2016 May;7:212-20; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000702165	SCV003807189	likely pathogenic	Neurofibromatosis, type 1	2022-06-09	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3 supporting, PS4 supporting, PM2 moderated, PM6 moderated