Submissions for variant NM_000548.5(TSC2):c.2859dup (p.Lys954fs)

dbSNP: rs796053504

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000190060	SCV000243735	pathogenic	not provided	2013-04-25	criteria provided, single submitter	clinical testing	c.2859dupC: p.Lys954GlnfsX6 (K954Qfsx6) in exon 26 of the TSC2 gene (NM_000548.3). The normal sequence with the base that is duplicated in braces is: ACCCCC{dupC}AAAC.The c.2859dupC mutation in the TSC2 gene causes a frameshift starting with codon Lysine 954, changes this amino acid to a Glutamine residue and creates a premature Stop codon at position 6 of the new reading frame, denoted p.Lys954GlnfsX6. This mutation is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Although this mutation has not been previously reported to our knowledge, it is considered a disease-causing mutation.The variant is found in INFANT-EPI panel(s).
Invitae	RCV000805489	SCV000945446	uncertain significance	Tuberous sclerosis 2	2023-12-07	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys954Glnfs*6) in the TSC2 gene. Loss-of-function variants in TSC2 are known to be pathogenic (PMID: 10205261, 17304050). However, tissue-specific alternative splicing of TSC2 gene results in a functional isoform lacking in-frame exon 26 (also known as exon 25, PMID: 26703369). For this reason the clinical significance of loss of function variants in exon 26 is currently uncertain. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with epilepsy (PMID: 26703369, 29655203). ClinVar contains an entry for this variant (Variation ID: 207774). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Genome-Nilou Lab	RCV000805489	SCV002039696	likely pathogenic	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002433860	SCV002752771	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-19	criteria provided, single submitter	clinical testing	The c.2859dupC variant, located in coding exon 25 of the TSC2 gene, results from a duplication of C at nucleotide position 2859, causing a translational frameshift with a predicted alternate stop codon (p.K954Qfs*6). This alteration has been identified in at least one patient with epilepsy (Ekong R et al. Hum Mutat, 2016 Apr;37:364-70; Lindy AS et al. Epilepsia, 2018 05;59:1062-1071). This alteration is expected to result in protein truncation or nonsense-mediated mRNA decay. However, this variant occurs in an exon that is absent in biologically relevant transcripts (Ekong R et al. Hum. Mutat., 2016 Apr;37:364-70). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Baylor Genetics	RCV003462295	SCV004206861	uncertain significance	Isolated focal cortical dysplasia type II	2023-08-28	criteria provided, single submitter	clinical testing