Submissions for variant NM_152906.7(TANGO2):c.460G>A (p.Gly154Arg)

gnomAD frequency: 0.00001  dbSNP: rs752298579

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV000210033	SCV000245441	pathogenic	Cardiac arrhythmia; Seizure; Intellectual disability; Episodic flaccid weakness; Acute rhabdomyolysis	2015-09-01	criteria provided, single submitter	clinical testing	Pathogenicity based on finding the variant in the homozygous state in 4 individuals, and in 1 compound heterozygote, all affected with a similar condition of recurrent rhabdomyolysis, intellectual disability, seizures, recurrent episodes of muscle weakness and metabolic crises, and cardiac arrhythmia.
Undiagnosed Diseases Network, NIH	RCV000210337	SCV000622160	pathogenic	Recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome	2016-04-11	criteria provided, single submitter	clinical testing	This variant has been described in multiple affected individuals (PMID 26805781)
Department of Molecular and Human Genetics, Baylor College of Medicine	RCV000210337	SCV001334075	pathogenic	Recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome	2020-04-16	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000210337	SCV001999936	likely pathogenic	Recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome	2021-05-21	criteria provided, single submitter	curation	The p.Gly154Arg variant in TANGO2 has been reported in 7 individuals with metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration (MECRCN) (PMID: 26805781, 29369572, 32576985) and has been identified in in 0.07% (1/33224) Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs752298579). 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#: 208823) and has been interpreted as Pathogenic by Baylor Genetics, OMIM, GeneReviews, Undiagnosed Diseases Network (NIH), and Department of Molecular and Human Genetics (Baylor College of Medicine). In vitro functional studies provide some evidence that the p.Gly154Arg variant may impact protein function (PMID: 26805781). However, these types of assays may not accurately represent biological function. Of the 7 affected individuals, 4 of those were homozygotes and 3 were compound heterozygotes that carried a reported pathogenic variant in trans, which increases the likelihood that the p.Gly154Arg variant is pathogenic (Variation ID: 224770; PMID: 26805781, 32576985). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. 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: PM3_very-strong, PS3_moderate (Richards 2015).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001857677	SCV002215019	pathogenic	not provided	2024-01-03	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 154 of the TANGO2 protein (p.Gly154Arg). This variant is present in population databases (rs752298579, gnomAD 0.06%). This missense change has been observed in individual(s) with TANGO2-related conditions (PMID: 26805781). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 208823). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects TANGO2 function (PMID: 26805781). For these reasons, this variant has been classified as Pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV000210337	SCV004047293	pathogenic	Recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome		criteria provided, single submitter	clinical testing	The TANGO2 c.460G>A (p.Gly154Arg) variant has been reported in homozygous and compound heterozygous state in individuals affected with metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration (MECRCN) (Lalani SR et al; 2016, Lalani SR et al; 2018 ). The p.Gly154Arg variant is reported with the allele frequency of 0.01351% in gnomad Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic/ Likely Pathogenic. The amino acid Gly at position 154 is changed to a Arg changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Gly154Arg in TANGO2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Of the 7 affected individuals, 4 of those were homozygotes and 3 were compound heterozygotes that carried a reported pathogenic variant in trans, which increases the likelihood that the p.Gly154Arg variant is pathogenic (Lalani SR et al; 2016). For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000210337	SCV000266381	pathogenic	Recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome	2019-05-09	no assertion criteria provided	literature only
GeneReviews	RCV000210337	SCV000899268	not provided	Recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome		no assertion provided	literature only	Common variant in persons of Hispanic ethnicity from Latin America