Submissions for variant NM_000548.5(TSC2):c.2251C>T (p.Arg751Ter)

dbSNP: rs45517222

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000201032	SCV000255880	pathogenic	Tuberous sclerosis 2	2014-07-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000201032	SCV000544361	pathogenic	Tuberous sclerosis 2	2024-10-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg751*) in the TSC2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TSC2 are known to be pathogenic (PMID: 10205261, 17304050). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with tuberous sclerosis complex (PMID: 10205261, 22552000, 25281918). ClinVar contains an entry for this variant (Variation ID: 50131). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000519394	SCV000617348	pathogenic	not provided	2023-01-18	criteria provided, single submitter	clinical testing	Reported multiple times previously in association with tuberous sclerosis complex (TSC) (Jones et al., 1999; TSC2 LOVD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32211034, 25281918, 22552000, 25525159, 10205261, 24271014, 31273045, 33528079)
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000201032	SCV000782402	pathogenic	Tuberous sclerosis 2	2016-11-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763365	SCV000894061	pathogenic	Lymphangiomyomatosis; Isolated focal cortical dysplasia type II; Tuberous sclerosis 2	2018-10-31	criteria provided, single submitter	clinical testing
Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University	RCV000201032	SCV001364426	pathogenic	Tuberous sclerosis 2	2022-07-19	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000201032	SCV002040951	pathogenic	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002444499	SCV002735179	pathogenic	Hereditary cancer-predisposing syndrome	2023-10-03	criteria provided, single submitter	clinical testing	The c.2251C>T (p.R751*) alteration, located in coding exon 20 of the TSC2 gene, consists of a C to T substitution at nucleotide position 2251. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 751. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been observed in multiple individuals with a personal and/or family history that is consistent with TSC2-related disease (Jones, 1999; Kacerovska, 2012; Ambry internal data). This variant has been determined to be the result of a de novo mutation in one child with features consistent with Tuberous sclerosis (Ding, 2020). Based on the available evidence, this alteration is classified as pathogenic.
Baylor Genetics	RCV004566812	SCV005054513	pathogenic	Isolated focal cortical dysplasia type II	2023-11-13	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000763365	SCV005415977	pathogenic	Lymphangiomyomatosis; Isolated focal cortical dysplasia type II; Tuberous sclerosis 2		criteria provided, single submitter	clinical testing	PVS1+PS4_Supporting+PM2_Supporting
Tuberous sclerosis database (TSC2)	RCV000043398	SCV000067204	not provided	Tuberous sclerosis syndrome		no assertion provided	curation