Submissions for variant NM_152906.7(TANGO2):c.94C>T (p.Arg32Ter)

gnomAD frequency: 0.00006  dbSNP: rs199801224

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000435649	SCV000514846	pathogenic	not provided	2022-09-28	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: 32552793, 32573669, 32929747, 33144682, 27711071, 30245509)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825574	SCV000966908	pathogenic	Recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome	2018-12-13	criteria provided, single submitter	clinical testing	The p.Arg32X variant in TANGO2 has been reported in the homozygous state in 2 in dividuals and in the compound heterozygous state in 1 individual with TANGO2-rel ated disorders and segregated with disease in 1 affected individual (Shamseldin 2017, Dines 2018). It has also been identified in 0.02% (4/24966) of African chr omosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant lea ds to a premature termination codon at position 32, which is predicted to lead t o a truncated or absent protein. Biallelic loss of function of the TANGO2 gene i s strongly associated to autosomal recessive TANGO2-related disorders. In summar y, this variant meets criteria to be classified as pathogenic for autosomal rece ssive TANGO2-related disorders. ACMG/AMP criteria applied: PVS1, PM2_Supporting, PP1, PM3.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000825574	SCV001244967	pathogenic	Recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome	2018-03-30	criteria provided, single submitter	clinical testing	A homozygous nonsense variant, NM_152906.6(TANGO2):c.94C>T , has been identified in exon 3 of 9 of the TANGO2 gene. The variant is predicted to result in a premature stop codon at position 32 of the protein (NP_690870.3(TANGO2):p.(Arg32*)), likely causing non-sense mediated decay. This variant is predicted to result in loss of protein function either through truncation (majority of the protien) or nonsense-mediated decay, which is a reported mechanism of pathogenicity for this gene. The variant is present in the gnomAD database at a frequency of 0.002888% (8 heterozygous, 0 homozygous). It has previously been described as pathogenic in ClinVar by a single submitter. Multiple nonsense variants downstream of p.Arg32 have also previously been described as pathogenic (Decipher, ClinVar). Analysis of parental samples confirmed parents to be carriers of this variant. Based on the information available at the time of curation, this variant has been classified as PATHOGENIC.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000825574	SCV001999898	pathogenic	Recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome	2021-05-21	criteria provided, single submitter	curation	The p.Arg32Ter variant in TANGO2 has been reported in 6 individuals with metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration (MECRCN) (PMID: 27711071, 30245509, 32573669, 32929747), and has been identified in 0.016% (4/24966) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs199801224). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID#: 378700) and has been interpreted as pathogenic by GeneDx, Laboratory for Molecular Medicine (Partners HealthCare Personalized Medicine), Victorian Clinical Genetics Services (Murdoch Childrens Research Institute), and Baylor Genetics. Of the 6 affected individuals, 3 of those were homozygotes, 1 was a compound heterozygote that carried a reported pathogenic variant in trans, and 2 siblings were compound heterozygotes that carried a variant of uncertain significance in trans, which increases the likelihood that the p.Arg32Ter variant is pathogenic (Variation ID: 224770; PMID: 32929747, 30245509). This nonsense variant leads to a premature termination codon at position 32, which is predicted to lead to a truncated or absent protein. Loss of function of the TANGO2 gene is strongly associated to autosomal recessive MECRCN. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive MECRCN. ACMG/AMP Criteria applied: PM3_strong, PVS1_strong (Richards 2015)
Revvity Omics, Revvity	RCV000825574	SCV002016844	likely pathogenic	Recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome	2021-09-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000435649	SCV002238597	pathogenic	not provided	2024-03-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg32*) 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 (rs199801224, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with clinical features of TANGO2-related conditions (PMID: 27711071, 30245509, 32573669). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 378700). For these reasons, this variant has been classified as Pathogenic.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000825574	SCV004804926	pathogenic	Recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome	2024-03-17	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000825574	SCV005422824	pathogenic	Recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome	2024-10-30	criteria provided, single submitter	clinical testing	Variant summary: TANGO2 c.94C>T (p.Arg32X) 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 2.8e-05 in 251182 control chromosomes. c.94C>T has been reported in the literature in individuals affected with Recurrent Metabolic Encephalomyopathic Crises-Rhabdomyolysis Arrhythmia-Intellectual Disability Syndrome (Lunke_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 32573669). ClinVar contains an entry for this variant (Variation ID: 378700). Based on the evidence outlined above, the variant was classified as pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000825574	SCV005900620	pathogenic	Recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome	2024-08-30	criteria provided, single submitter	clinical testing	This nonsense variant found in exon 3 of 9 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Loss-of-function variation in TANGO2 is an established mechanism of disease (PMID: 26805782). This variant has been previously reported as a compound heterozygous and homozygous change in patients with TANGO2 deficiency (PMID: 32573669, 30245509, 27711071). The c.94C>T (p.Arg32Ter) variant is present in the latest version of the gnomAD population database at an allele frequency of 0.002% (25/1613662), and is absent in the homozygous state, thus is presumed to be rare. Based on the available evidence, c.94C>T (p.Arg32Ter) is classified as Pathogenic.