Submissions for variant NM_001163435.3(TBCK):c.376C>T (p.Arg126Ter)

gnomAD frequency: 0.00023  dbSNP: rs575822089

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000256086	SCV000322131	pathogenic	not provided	2021-11-15	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; This variant is associated with the following publications: (PMID: 27040692, 27040691, 29283439, 30577886)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000210864	SCV000697751	pathogenic	Hypotonia, infantile, with psychomotor retardation and characteristic facies 3	2019-10-25	criteria provided, single submitter	clinical testing	Variant summary: TBCK c.376C>T (p.Arg126X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 7.7e-05 in 142542 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in TBCK causing Hypotonia, infantile, with psychomotor retardation and characteristic facies 3 (7.7e-05 vs 0.0011). c.376C>T has been reported in the literature in multiple individuals, predominantly of Puerto Rican descent (in compound heterozygous or homozygous state) affected with Hypotonia, infantile, with psychomotor retardation and characteristic facies 3 (Chong_2016, Bhoj_2016, Ortiz-Gonzlez_2018). These data indicate that the variant is very likely to be associated with disease. Chong_2016 reports the variant perturbs the levels of both major TBCK protein isoforms in fibroblasts. Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV000623429	SCV000741301	pathogenic	Inborn genetic diseases	2021-10-01	criteria provided, single submitter	clinical testing	The c.376C>T (p.R126*) alteration, located in exon 4 (coding exon 3) of the TBCK gene, consists of a C to T substitution at nucleotide position 376. This changes the amino acid from a Arginine (R) to a stop codon at amino acid position 126. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the T allele has an overall frequency of 0.007% (13/173798) total alleles studied. This alteration has been described in the homozygous state and compound heterozygous with a second TBCK variant in multiple unrelated individuals, primarily of Puerto Rican descent (Bhoj, 2016; Chong, 2016; Ortiz-Gonzalez, 2018; Baker, 2019; Ziats, 2020). Additionally, we have identified this variant in the homozygous state via whole exome sequencing at Ambry Genetics in four patients with clinical features of TBCK-related neurodevelopmental disorders. Based on the available evidence, this alteration is classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000210864	SCV000894330	pathogenic	Hypotonia, infantile, with psychomotor retardation and characteristic facies 3	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV000256086	SCV001416598	pathogenic	not provided	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg126*) in the TBCK gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TBCK are known to be pathogenic (PMID: 27040692, 30103036). This variant is present in population databases (rs575822089, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with TBCK-related severe infantile syndromic encephalopathy or TBCK-related intellectual disability and hypotonia syndrome (PMID: 27040691, 27040692). ClinVar contains an entry for this variant (Variation ID: 225235). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000210864	SCV001522071	pathogenic	Hypotonia, infantile, with psychomotor retardation and characteristic facies 3	2019-12-17	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
New York Genome Center	RCV000210864	SCV002099224	pathogenic	Hypotonia, infantile, with psychomotor retardation and characteristic facies 3	2021-08-26	criteria provided, single submitter	clinical testing	The c.376C>T (p.Arg126Ter) variant identified in the TBCK gene results in the premature termination of the protein at amino acid 126/894 (coding exon 4/26). This is predicted to lead to the termination of the protein within the protein kinase domain and result in the absence of Rab-GAP TBC and RHOD domains. This variant is found with low frequency in gnomAD (13 heterozygotes, 0 homozygotes; allele frequency: 7.48e-5) suggesting it is not a common benign variant in the populations represented in this database. This variant is reported as Pathogenic/Likely Pathogenic in ClinVar (VarID:225235), and has been reported in more than 10 affected individuals in the literature [PMID:27040692; PMID:27040691; PMID:29283439; PMID:31618753] in both homozygosity [PMID:27040692; PMID:27040691; PMID:29283439] and in compound heterozygosity with a second pathogenic variant [PMID:27040691; PMID:29283439]. Functional studies suggest this variant leads to increased levels of autophagic flux. This variant was identifed in homozygosity in an individual submitted for clinical WGS. Given the deleterious nature of the homozygous c.376C>T (p.Arg126Ter) variant identified in this individual, its low frequency in population databases, and the observation in many affected individuals in the literature, it is reported here as Pathogenic.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000210864	SCV002583799	pathogenic	Hypotonia, infantile, with psychomotor retardation and characteristic facies 3	2022-07-29	criteria provided, single submitter	clinical testing	PVS1, PM2, PM3
OMIM	RCV000210864	SCV000267182	pathogenic	Hypotonia, infantile, with psychomotor retardation and characteristic facies 3	2016-05-19	no assertion criteria provided	literature only
University of Washington Center for Mendelian Genomics, University of Washington	RCV000755061	SCV000882879	likely pathogenic	Syndromic Infantile Encephalopathy	2016-04-07	no assertion criteria provided	research
GenomeConnect, ClinGen	RCV000210864	SCV001423286	not provided	Hypotonia, infantile, with psychomotor retardation and characteristic facies 3		no assertion provided	phenotyping only	Variant interpretted as Pathogenic and reported on 08-19-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000210864	SCV001469126	pathogenic	Hypotonia, infantile, with psychomotor retardation and characteristic facies 3	2020-08-07	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000256086	SCV001742154	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000256086	SCV001932487	pathogenic	not provided		no assertion criteria provided	clinical testing