Submissions for variant NM_001042492.3(NF1):c.4977_4980del (p.Lys1661fs)

dbSNP: rs1085307459

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000489809	SCV000576493	pathogenic	not provided	2018-02-21	criteria provided, single submitter	clinical testing	The c.4914_4917delCTCT variant in the NF1 gene has been reported previously in association with neurofibromatosis type 1 (Side et al., 1997; Uusitalo et al., 2014; Esposito et al., 2015). The deletion causes a frameshift starting with codon Lysine 1640, changes this amino acid to a Glycine residue and creates a premature Stop codon at position 36 of the new reading frame, denoted p.Lys1640GlyfsX36. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In summary, we consider this variant to be pathogenic.
Ambry Genetics	RCV000492080	SCV000581248	pathogenic	Hereditary cancer-predisposing syndrome	2014-06-13	criteria provided, single submitter	clinical testing	The c.4977_4980delCTCT(also known as c.4914delCTCT) pathogenic mutation, located in coding exon 37 of the NF1 gene, results from a deletion of 4 nucleotides between nucleotide positions 4977 and 4980, causing a translational frameshift with a predicted alternate stop codon (<span style="background-color: initial;">p.K1661Gfs*36)<span style="background-color: initial;">. This pathogenic mutation was first identified in a 10 month old child with NF1 and acute myeloid leukemia; the child inherited the mutation from his father, who also had NF1 (<span data-redactor="verified" style="background-color: initial;">Side L et al. N Engl J Med. 1997; 336(24):1713-20). In addition to the clinical data presented in the literature, s<span data-redactor="verified" style="background-color: initial;">ince frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294).
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000660069	SCV000782038	pathogenic	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
Invitae	RCV000660069	SCV001200736	pathogenic	Neurofibromatosis, type 1	2023-12-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys1640Glyfs*36) in the NF1 gene. It is expected to result in an absent or disrupted protein product. 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). This premature translational stop signal has been observed in individuals with neurofibromatosis, type 1 (PMID: 9180088, 24676424, 26478990). This variant is also known as 4914delCTCT. ClinVar contains an entry for this variant (Variation ID: 426127). For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000660069	SCV002560095	pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
3billion	RCV000660069	SCV002573159	pathogenic	Neurofibromatosis, type 1	2022-09-01	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Frameshift variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000426127 / PMID: 9180088). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Neuberg Centre For Genomic Medicine, NCGM	RCV000660069	SCV004100507	pathogenic	Neurofibromatosis, type 1		criteria provided, single submitter	clinical testing	The frameshift deletion p.K1640Gfs*36 in NF1 (NM_000267.3) has been reported in affected individuals (Side et al., 1997; Uusitalo et al., 2014; Esposito et al., 2015). It has been submitted to ClinVar as Pathogenic.The p.K1640Gfs*36 variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation. For these reasons, this variant has been classified as Pathogenic.