Submissions for variant NM_001904.4(CTNNB1):c.998dup (p.Tyr333Ter)

dbSNP: rs886041281

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000300794	SCV000329621	pathogenic	not provided	2021-03-12	criteria provided, single submitter	clinical testing	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 in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 27915094, 28726809, 26502894, 28135719, 28191889)
CeGaT Center for Human Genetics Tuebingen	RCV000300794	SCV001248661	pathogenic	not provided	2018-03-01	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000300794	SCV001762258	pathogenic	not provided	2021-06-17	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000985149	SCV002026407	pathogenic	Severe intellectual disability-progressive spastic diplegia syndrome	2021-10-13	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PVS1, PS2, PS4_MOD, PM2_SUP
3billion	RCV000985149	SCV002059146	pathogenic	Severe intellectual disability-progressive spastic diplegia syndrome	2022-01-03	criteria provided, single submitter	clinical testing	Stop-gained (nonsense): 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 (PVS1_VS).The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000279956, PMID:26502894, 3billion dataset). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). The variant has been previously reported as de novo in a similarly affected individual (PMID: 25533962, PS2_S). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Invitae	RCV000300794	SCV002239128	pathogenic	not provided	2021-12-20	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 279956). This premature translational stop signal has been observed in individual(s) with CTNNB1-related conditions (PMID: 26502894, 27915094). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr333*) in the CTNNB1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CTNNB1 are known to be pathogenic (PMID: 23033978, 24614104, 25326669, 26350204, 28575650).
PreventionGenetics, part of Exact Sciences	RCV003417873	SCV004114203	pathogenic	CTNNB1-related disorder	2022-11-07	criteria provided, single submitter	clinical testing	The CTNNB1 c.998dupA variant is predicted to result in premature protein termination (p.Tyr333*). This variant has been reported to occur de novo in individuals with CTNNB1-related neurodevelopmental disorders (Supp. Figure 31 in Prasad et al 2016. PubMed ID: 26502894; Patient 10 in Kharbanda M et al 2016. PubMed ID: 27915094; Proband 12 in Strauss KA et al 2017. PubMed ID: 28726809; Table S2 in Turner TN et al 2019. PubMed ID: 31785789). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in CTNNB1 are expected to be pathogenic. This variant is interpreted as pathogenic.
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000985149	SCV001133139	pathogenic	Severe intellectual disability-progressive spastic diplegia syndrome	2019-09-26	no assertion criteria provided	clinical testing