Submissions for variant NM_000548.5(TSC2):c.4839CAT[1] (p.Ile1614del)

dbSNP: rs137854331

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics Inc	RCV001283509	SCV000255905	pathogenic	not provided	2019-12-04	criteria provided, single submitter	clinical testing	Not found in the total gnomAD dataset, and the data is high quality. Located in potentially critical domain of the protein. Found in multiple individuals with expected phenotype for this gene. 3 de novo cases with parental identity not confirmed.
Invitae	RCV000201210	SCV001222548	pathogenic	Tuberous sclerosis 2	2022-09-07	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 49325). This variant is also known as del (4770-4772); dl Ile 1591. This variant has been observed in individual(s) with tuberous sclerosis complex (PMID: 9463313, 22748302; Invitae). This variant is not present in population databases (gnomAD no frequency). This variant, c.4842_4844del, results in the deletion of 1 amino acid(s) of the TSC2 protein (p.Ile1614del), but otherwise preserves the integrity of the reading frame. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001283509	SCV001818339	pathogenic	not provided	2020-06-10	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); In-frame deletion of 1 amino acids in a non-repeat region; This variant is associated with the following publications: (PMID: 17304050, 22867869, 25782670, 22748302, 9463313)
3billion	RCV000201210	SCV003841872	pathogenic	Tuberous sclerosis 2	2023-02-23	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Inframe deletion located in a nonrepeat region was predicted to change the length of the protein and disrupt normal protein function. The variant has been observed in at least two similarly affected unrelated individuals (PMID: 22748302, 9463313). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000049325 / PMID: 9463313). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Tuberous sclerosis database (TSC2)	RCV000042585	SCV000066379	not provided	Tuberous sclerosis syndrome		no assertion provided	curation
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001283509	SCV001744482	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001283509	SCV001963954	pathogenic	not provided		no assertion criteria provided	clinical testing