NM_152906.7(TANGO2):c.460G>A (p.Gly154Arg) AND Recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome

Germline classification:: Pathogenic/Likely pathogenic (6 submissions)
Last evaluated:: May 21, 2021
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000210337.18

Allele description [Variation Report for NM_152906.7(TANGO2):c.460G>A (p.Gly154Arg)]

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

Gene:

TANGO2:transport and golgi organization 2 homolog [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

22q11.21

Genomic location:

Preferred name:

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

Other names:

NM_152906.7(TANGO2):c.460G>A

HGVS:

NC_000022.11:g.20061538G>A
NG_046857.1:g.49539G>A
NM_001283106.3:c.460G>A
NM_001283116.3:c.460G>A
NM_001283129.3:c.583G>A
NM_001283148.3:c.460G>A
NM_001283154.3:c.460G>A
NM_001283179.3:c.274G>A
NM_001283186.3:c.274G>A
NM_001283199.3:c.381-1800G>A
NM_001283215.3:c.575-3004G>A
NM_001283235.3:c.166G>A
NM_001283248.3:c.266-1800G>A
NM_001322141.2:c.583G>A
NM_001322142.2:c.460G>A
NM_001322143.2:c.583G>A
NM_001322144.2:c.583G>A
NM_001322145.2:c.397G>A
NM_001322146.2:c.358G>A
NM_001322147.2:c.397G>A
NM_001322148.2:c.358G>A
NM_001322149.2:c.504-1800G>A
NM_001322150.2:c.166G>A
NM_001322153.2:c.166G>A
NM_001322155.2:c.166G>A
NM_001322160.2:c.358G>A
NM_001322163.2:c.274G>A
NM_001322166.2:c.274G>A
NM_001322167.2:c.274G>A
NM_001322169.2:c.274G>A
NM_001322171.2:c.166G>A
NM_001322172.2:c.166G>A
NM_001322173.2:c.166G>A
NM_001322174.2:c.166G>A
NM_001322175.2:c.166G>A
NM_152906.7:c.460G>AMANE SELECT
NP_001270035.1:p.Gly154Arg
NP_001270045.1:p.Gly154Arg
NP_001270058.1:p.Gly195Arg
NP_001270077.1:p.Gly154Arg
NP_001270083.1:p.Gly154Arg
NP_001270108.1:p.Gly92Arg
NP_001270115.1:p.Gly92Arg
NP_001270164.1:p.Gly56Arg
NP_001309070.1:p.Gly195Arg
NP_001309071.1:p.Gly154Arg
NP_001309072.1:p.Gly195Arg
NP_001309073.1:p.Gly195Arg
NP_001309074.1:p.Gly133Arg
NP_001309075.1:p.Gly120Arg
NP_001309076.1:p.Gly133Arg
NP_001309077.1:p.Gly120Arg
NP_001309079.1:p.Gly56Arg
NP_001309082.1:p.Gly56Arg
NP_001309084.1:p.Gly56Arg
NP_001309089.1:p.Gly120Arg
NP_001309092.1:p.Gly92Arg
NP_001309095.1:p.Gly92Arg
NP_001309096.1:p.Gly92Arg
NP_001309098.1:p.Gly92Arg
NP_001309100.1:p.Gly56Arg
NP_001309101.1:p.Gly56Arg
NP_001309102.1:p.Gly56Arg
NP_001309103.1:p.Gly56Arg
NP_001309104.1:p.Gly56Arg
NP_690870.3:p.Gly154Arg
NC_000022.10:g.20049061G>A
NC_000022.10:g.20049061G>A
NM_152906.4:c.460G>A
NM_152906.5:c.460G>A
NM_152906.6:c.460G>A
NR_136206.2:n.450G>A
NR_136211.2:n.636G>A
NR_136212.1:n.557G>A
Q6ICL3:p.Gly154Arg
p.G154R

Protein change:

G120R; GLY154ARG

Links:

UniProtKB: Q6ICL3#VAR_076912; OMIM: 616830.0001; dbSNP: rs752298579

NCBI 1000 Genomes Browser:

rs752298579

Molecular consequence:

NM_001283199.3:c.381-1800G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001283215.3:c.575-3004G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001283248.3:c.266-1800G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001322149.2:c.504-1800G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001283106.3:c.460G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001283116.3:c.460G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001283129.3:c.583G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001283148.3:c.460G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001283154.3:c.460G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001283179.3:c.274G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001283186.3:c.274G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001283235.3:c.166G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322141.2:c.583G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322142.2:c.460G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322143.2:c.583G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322144.2:c.583G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322145.2:c.397G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322146.2:c.358G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322147.2:c.397G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322148.2:c.358G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322150.2:c.166G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322153.2:c.166G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322155.2:c.166G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322160.2:c.358G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322163.2:c.274G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322166.2:c.274G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322167.2:c.274G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322169.2:c.274G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322171.2:c.166G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322172.2:c.166G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322173.2:c.166G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322174.2:c.166G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001322175.2:c.166G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_152906.7:c.460G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_136206.2:n.450G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_136211.2:n.636G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_136212.1:n.557G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

Condition(s)

Name:: Recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome (MECRCN)
Synonyms:: Metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration; METABOLIC CRISES, RECURRENT, WITH RHABDOMYOLYSIS, CARDIAC ARRHYTHMIAS, AND NEURODEGENERATION
Identifiers:: MONDO: MONDO:0018820; MedGen: C5567524; OMIM: 616878

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000266381	OMIM	no assertion criteria provided	Pathogenic (May 9, 2019)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000622160	Undiagnosed Diseases Network, NIH	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 11, 2016)	paternal	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000899268	GeneReviews	no classification provided	not provided	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 26805781, 29369572
SCV001334075	Department of Molecular and Human Genetics, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 16, 2020)	inherited	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25741868, 32576985
SCV001999936	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 21, 2021)	germline	curation	PubMed (2) [See all records that cite these PMIDs] 26805781, 25741868
SCV004047293	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	inherited	yes	1	1	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	literature only, curation
Mexican American	paternal	yes	1	not provided	not provided	not provided	no	clinical testing

Citations

PubMed

TANGO2 Deficiency.

Miyake CY, Burrage L, Glinton K, Houck K, Hoyos-Martinez A, Graham B, Yang Y, Rawls-Castillo B, Scaglia F, Soler-Alfonso C, Lalani SR.

2018 Jan 25 [updated 2023 Mar 9]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(®) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.

PubMed [citation]

PMID:: 29369572

CNVs cause autosomal recessive genetic diseases with or without involvement of SNV/indels.

Yuan B, Wang L, Liu P, Shaw C, Dai H, Cooper L, Zhu W, Anderson SA, Meng L, Wang X, Wang Y, Xia F, Xiao R, Braxton A, Peacock S, Schmitt E, Ward PA, Vetrini F, He W, Chiang T, Muzny D, Gibbs RA, et al.

Genet Med. 2020 Oct;22(10):1633-1641. doi: 10.1038/s41436-020-0864-8. Epub 2020 Jun 24.

PubMed [citation]

PMID:: 32576985
PMCID:: PMC8445517

See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000266381.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In affected members of 4 Hispanic families (families 1, 3, 4, and 5) with recurrent metabolic crises with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration (MECRCN; 616878), Lalani et al. (2016) identified homozygosity for a c.460G-A transition (SCV000245441) in exon 7 of the TANGO2 gene, resulting in a gly154-to-arg (G154R) substitution at a highly conserved residue. The mutation segregated with disease in the 3 families for which parental DNA was available. The authors noted that the G154R variant was enriched in the Hispanic/Latino population, with a minor allele frequency of 0.26% in the ExAC database (overall frequency, 0.02%); however, no G154R homozygotes had been reported in the ExAC, 1000 Genomes Project, dbSNP (build 134), or NHLBI GO Exome Sequencing Project databases. Patient fibroblasts showed evidence of increased endoplasmic reticulum stress and a reduction in Golgi volume density compared to control, suggesting that disruptions in TANGO2 result in an imbalance in the vesicular pathway. Lalani et al. (2016) also studied an affected 6-year-old girl from a family of Hispanic/European origin, who was compound heterozygous for the G154R mutation and an approximately 34-bp deletion (616830.0002) in the TANGO2 gene.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Undiagnosed Diseases Network, NIH, SCV000622160.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Mexican American	1	not provided	no	clinical testing	PubMed (1)

Description

This variant has been described in multiple affected individuals (PMID 26805781)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	paternal	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From GeneReviews, SCV000899268.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

Common variant in persons of Hispanic ethnicity from Latin America

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Department of Molecular and Human Genetics, Baylor College of Medicine, SCV001334075.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (2)

Description

in trans with TANGO2 exons 3-9 deletion

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	inherited	yes	not provided	not provided	not provided		1	not provided	1	not provided

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001999936.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (2)

Description

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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Neuberg Centre For Genomic Medicine, NCGM, SCV004047293.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 6, 2024

ClinVar

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