Submissions for variant NM_152906.7(TANGO2):c.256C>T (p.Arg86Ter)

gnomAD frequency: 0.00001  dbSNP: rs1162037663

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Medicine Lab, University of California San Francisco	RCV000754642	SCV000882572	pathogenic	Recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome	2018-03-26	criteria provided, single submitter	clinical testing	A reportable homozygous variant in the TANGO2 gene, c.256C>T, p.R86*, was identified at chromosomal position chr22: 20040098 (hg19). The TANGO2 gene encodes for a Transport and Golgi Organization (TANGO)protein that localizes to the Golgi and cytoplasm. Variants in this gene are associated with metabolic encephalomyopathic crises, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration (MIM: 616878). Sixteen patients with biallelic variants in TANGO2 and an overlapping phenotype have been described to date consistently with autosomal recessive inheritance (Kramer et al. 2016; Lalani et al. 2016; Shamseldin et al. 2017). Functional studies in Kremer et al. suggest a functional defect in mitochondrial beta-oxidation of fatty acid consistent with the biochemical presentation of most patients described. Impairment of Golgi organization has also been speculated to be relevant or the pathogenesis of the phenotypic presentation of individuals with biallelic TANGO2 pathogenic variants (Lalani et al. 2016). The majority of patients identified to date harbor homozygous or compound heterozygous loss of function variants in TANGO2; a common missense has also been described. The c.256C>T (p.R86*) variant has not been previously reported in affected individuals but it is a loss of function homozygous variant consistent with recessive inheritance and previously described pathogenic variants in this gene. This variant is a rare variant, and is not present in the 1000 Genomes, or ExAC population sequencing projects. In the gnomAD population sequencing project, there is a single heterozygous individual (1 out of 174932 alleles), and no homozygous individuals reported.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000754642	SCV001999931	likely pathogenic	Recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome	2021-05-21	criteria provided, single submitter	curation	The p.Arg86Ter variant in TANGO2 has been reported in 3 siblings with metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration (MECRCN) (PMID: 32929747), segregated with disease in these siblings from 1 family (PMID: 32929747), and has been identified in 0.006% (1/16414) of European (Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1162037663). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#: 617515) and has been interpreted as Pathogenic by Genomic Medicine Lab (University of California San Francisco). This nonsense variant leads to a premature termination codon at position 86, which is predicted to lead to a truncated or absent protein. Loss of function of the TANGO2 gene is a strongly established disease mechanism in autosomal recessive MECRCN. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive MECRCN. ACMG/AMP Criteria applied: PVS1_strong, PP1, PM2_supporting, PP3_supporting (Richards 2015).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001855851	SCV002240788	pathogenic	not provided	2024-01-15	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg86*) in the TANGO2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TANGO2 are known to be pathogenic (PMID: 26805781, 26805782). This variant is present in population databases (no rsID available, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with TANGO2-related conditions (PMID: 32929747). ClinVar contains an entry for this variant (Variation ID: 617515). For these reasons, this variant has been classified as Pathogenic.
New York Genome Center	RCV000754642	SCV002564355	pathogenic	Recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome	2021-09-14	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000754642	SCV003921844	pathogenic	Recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome	2023-07-16	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with recurrent metabolic encephalomyopathic crises with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration (MECRCN; MIM#616878). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (1 heterozygote, 0 homozygotes). (SP) 0702 - Other NMD-predicted variants comparable to the one identified in this case have strong previous evidence for pathogenicity. More than five other variants predicted to result in a loss of function have previously been reported in individuals with MECRCN (ClinVar, DECIPHER). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported as pathogenic in ClinVar and in the homozygous state in at least two unrelated individuals with MECRCN (ClinVar, PMID: 32929747). (SP) 0903 - This variant has limited evidence for segregation with disease. The variant has previously been observed to segregate in three homozygous siblings affected with MECRCN (PMID: 32929747). (SP) 1101 - Very strong and specific phenotype match for this individual. (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000754642	SCV005726356	pathogenic	Recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome	2024-11-13	criteria provided, single submitter	clinical testing	Variant summary: TANGO2 c.256C>T (p.Arg86X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 5.5e-06 in 180380 control chromosomes (gnomAD). c.256C>T has been reported in the literature in individuals affected with Recurrent Metabolic Encephalomyopathic Crises-Rhabdomyolysis Arrhythmia-Intellectual Disability Syndrome (e.g. Lunke_2023). The following publication has been ascertained in the context of this evaluation (PMID: 37291213). ClinVar contains an entry for this variant (Variation ID: 617515). Based on the evidence outlined above, the variant was classified as pathogenic.