Submissions for variant NM_001163435.3(TBCK):c.1897+1G>A

gnomAD frequency: 0.00002  dbSNP: rs374319146

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV000210876	SCV001522066	pathogenic	Hypotonia, infantile, with psychomotor retardation and characteristic facies 3	2019-12-19	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001814075	SCV001755214	pathogenic	Abnormality of the nervous system	2021-07-10	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000210876	SCV002018935	pathogenic	Hypotonia, infantile, with psychomotor retardation and characteristic facies 3	2021-02-07	criteria provided, single submitter	clinical testing
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000210876	SCV002072920	pathogenic	Hypotonia, infantile, with psychomotor retardation and characteristic facies 3		criteria provided, single submitter	clinical testing	The splice donor variant c.1897+1G>A in TBCK (NM_001163435.3) has been previously reported in affected patients (Bhoj E et al). The variant has been submitted to ClinVar as Pathogenic/Likely pathogenic. The c.1897+1G>A variant is observed in 2/29,354 (0.0068%) alleles from individuals of Latino background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant affects an invariant splice nucleotide and is predicted to cause loss of function. Loss of function mutations have been reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.
3billion	RCV000210876	SCV002521425	pathogenic	Hypotonia, infantile, with psychomotor retardation and characteristic facies 3	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function 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: VCV000183338). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Invitae	RCV002516437	SCV003525523	pathogenic	not provided	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 21 of the TBCK gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TBCK are known to be pathogenic (PMID: 27040692, 30103036). 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. Disruption of this splice site has been observed in individual(s) with TBCK-related conditions (PMID: 25558065). This variant is also known as c.1708+1G>A. ClinVar contains an entry for this variant (Variation ID: 183338). Studies have shown that disruption of this splice site alters TBCK gene expression (PMID: 27040691). 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.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000210876	SCV004804719	pathogenic	Hypotonia, infantile, with psychomotor retardation and characteristic facies 3	2024-03-17	criteria provided, single submitter	research
Department Of Translational Genomics (developmental Genetics Section), King Faisal Specialist Hospital & Research Centre	RCV000162173	SCV000196459	likely pathogenic	Global developmental delay; Seizure; Ventral septal defect; Delayed reflexes; Dysmorphism; Hypotonia	2014-12-01	no assertion criteria provided	research
OMIM	RCV000210876	SCV000267181	pathogenic	Hypotonia, infantile, with psychomotor retardation and characteristic facies 3	2015-01-13	no assertion criteria provided	literature only