ClinVar Genomic variation as it relates to human health

In-frame deletion of 2 amino acids in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31121919, 10534774, 30530636, 21089070, 31370276, 31776437)

This variant, c.4973_4978del, results in the deletion of 2 amino acid(s) of the NF1 protein (p.Ile1658_Tyr1659del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with neurofibromatosis type 1 (PMID: 10534774, 30530636; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 431651). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic.

The c.4973_4978delTCTATA pathogenic mutation (also known as p.I1658_Y1659del) is located in coding exon 36 of the NF1 gene. This pathogenic mutation results from an in-frame TCTATA deletion at nucleotide positions 4973 to 4978. This results in the in-frame deletion of isoleucine and tyrosine at amino acid positions 1658 and 1659. This variant has been determined to be the result of a de novo mutation or germline mosaicism in one individual with NF1 (Ambry internal data). This variant has also been observed in literature in multiple individuals and families with clinical diagnosis of NF1 (Wu R et al. Genes Chromosomes Cancer 1999;26(4):376-80); (Giugliano T et al. Genes (Basel), 2019 07;10:); (Maani N et al. Cancers (Basel), 2019 May;11:); (Kang E et al. J Hum Genet, 2020 Jan;65:79-89). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). This amino acid region is well conserved in available vertebrate species. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

The NF1 c.5036_5041delTCTATA; p.Ile1679_Tyr1680del variant (rs1135402868), also known as 4973delTCTATA for NM_000267.3, is reported in the literature in multiple individuals with NF1 (Frayling 2019, Giugliano 2019, Maani 2019, Wu 1999), and is reported in ClinVar (Variation ID: 431651). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant deletes an isoleucine and tyrosine residue leaving the rest of the protein in-frame. Based on available information, this variant is considered to be likely pathogenic. References: Frayling IM et al. Breast cancer risk in neurofibromatosis type 1 is a function of the type of NF1 gene mutation: a new genotype-phenotype correlation. J Med Genet. 2019 Apr;56(4):209-219. PMID: 30530636. Giugliano T et al. Clinical and Genetic Findings in Children with Neurofibromatosis Type 1, Legius Syndrome, and Other Related Neurocutaneous Disorders. Genes (Basel). 2019 Jul 31;10(8):580. PMID: 31370276. Maani N et al. NF1 Patients Receiving Breast Cancer Screening: Insights from The Ontario High Risk Breast Screening Program. Cancers (Basel). 2019 May 22;11(5):707. PMID: 31121919. Wu R et al. Germline mutations in NF1 patients with malignancies. Genes Chromosomes Cancer. 1999 Dec;26(4):376-80. PMID: 10534774.