ClinVar Genomic variation as it relates to human health
NM_152906.7(TANGO2):c.460G>A (p.Gly154Arg)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_152906.7(TANGO2):c.460G>A (p.Gly154Arg)
Variation ID: 208823 Accession: VCV000208823.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 22q11.21 22: 20061538 (GRCh38) [ NCBI UCSC ] 22: 20049061 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Mar 15, 2016 Mar 5, 2024 Jan 3, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_152906.7:c.460G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_690870.3:p.Gly154Arg missense NM_001283106.3:c.460G>A NP_001270035.1:p.Gly154Arg missense NM_001283116.3:c.460G>A NP_001270045.1:p.Gly154Arg missense NM_001283129.3:c.583G>A NP_001270058.1:p.Gly195Arg missense NM_001283148.3:c.460G>A NP_001270077.1:p.Gly154Arg missense NM_001283154.3:c.460G>A NP_001270083.1:p.Gly154Arg missense NM_001283179.3:c.274G>A NP_001270108.1:p.Gly92Arg missense NM_001283186.3:c.274G>A NP_001270115.1:p.Gly92Arg missense NM_001283199.3:c.381-1800G>A intron variant NM_001283215.3:c.575-3004G>A intron variant NM_001283235.3:c.166G>A NP_001270164.1:p.Gly56Arg missense NM_001283248.3:c.266-1800G>A intron variant NM_001322141.2:c.583G>A NP_001309070.1:p.Gly195Arg missense NM_001322142.2:c.460G>A NP_001309071.1:p.Gly154Arg missense NM_001322143.2:c.583G>A NP_001309072.1:p.Gly195Arg missense NM_001322144.2:c.583G>A NP_001309073.1:p.Gly195Arg missense NM_001322145.2:c.397G>A NP_001309074.1:p.Gly133Arg missense NM_001322146.2:c.358G>A NP_001309075.1:p.Gly120Arg missense NM_001322147.2:c.397G>A NP_001309076.1:p.Gly133Arg missense NM_001322148.2:c.358G>A NP_001309077.1:p.Gly120Arg missense NM_001322149.2:c.504-1800G>A intron variant NM_001322150.2:c.166G>A NP_001309079.1:p.Gly56Arg missense NM_001322153.2:c.166G>A NP_001309082.1:p.Gly56Arg missense NM_001322155.2:c.166G>A NP_001309084.1:p.Gly56Arg missense NM_001322160.2:c.358G>A NP_001309089.1:p.Gly120Arg missense NM_001322163.2:c.274G>A NP_001309092.1:p.Gly92Arg missense NM_001322166.2:c.274G>A NP_001309095.1:p.Gly92Arg missense NM_001322167.2:c.274G>A NP_001309096.1:p.Gly92Arg missense NM_001322169.2:c.274G>A NP_001309098.1:p.Gly92Arg missense NM_001322171.2:c.166G>A NP_001309100.1:p.Gly56Arg missense NM_001322172.2:c.166G>A NP_001309101.1:p.Gly56Arg missense NM_001322173.2:c.166G>A NP_001309102.1:p.Gly56Arg missense NM_001322174.2:c.166G>A NP_001309103.1:p.Gly56Arg missense NM_001322175.2:c.166G>A NP_001309104.1:p.Gly56Arg missense NR_136206.2:n.450G>A non-coding transcript variant NR_136211.2:n.636G>A non-coding transcript variant NR_136212.1:n.557G>A non-coding transcript variant NC_000022.11:g.20061538G>A NC_000022.10:g.20049061G>A NG_046857.1:g.49539G>A Q6ICL3:p.Gly154Arg - Protein change
- G154R, G120R, G56R, G92R, G133R, G195R
- Other names
- NM_152906.7(TANGO2):c.460G>A
- Canonical SPDI
- NC_000022.11:20061537:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00014
Exome Aggregation Consortium (ExAC) 0.00023
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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TANGO2 | - | - |
GRCh38 GRCh37 |
431 | 801 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
criteria provided, single submitter
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Sep 1, 2015 | RCV000210033.2 | |
Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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May 21, 2021 | RCV000210337.18 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 3, 2024 | RCV001857677.4 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Sep 01, 2015)
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criteria provided, single submitter
Method: clinical testing, research
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Acute rhabdomyolysis
Episodic flaccid weakness Intellectual disability Seizures Arrhythmia (Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline,
maternal
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Baylor Genetics
Study: TANGO2
Accession: SCV000245441.1 First in ClinVar: Mar 15, 2016 Last updated: Mar 15, 2016 |
Comment:
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 … (more)
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. (less)
Observation 1:
Clinical Features:
Seizures (present) , Developmental regression (present) , Rhabdomyolysis (present) , Myoglobinuria (present) , Hypoglycemia (present) , Atrophy/Degeneration affecting the cerebrum (present) , Exotropia (present) , … (more)
Seizures (present) , Developmental regression (present) , Rhabdomyolysis (present) , Myoglobinuria (present) , Hypoglycemia (present) , Atrophy/Degeneration affecting the cerebrum (present) , Exotropia (present) , Microcephaly (present) , Myopathic facies (present) , Hypertonia (present) , Brisk reflexes (present) , Babinski sign (present) (less)
Family history: no
Age: 0-9 years
Sex: female
Ethnicity/Population group: Hispanic Americans
Observation 2:
Clinical Features:
Episodic metabolic acidosis (present) , Intermittent lactic acidemia (present) , Prolonged QTc interval (present) , Episodic flaccid weakness (present) , Abnormality of lateral ventricle (present) … (more)
Episodic metabolic acidosis (present) , Intermittent lactic acidemia (present) , Prolonged QTc interval (present) , Episodic flaccid weakness (present) , Abnormality of lateral ventricle (present) , Acute rhabdomyolysis (present) , Myoglobinuria (present) , Myopathic facies (present) , Dysarthria (present) , Ataxia (present) , Intellectual disability (present) (less)
Family history: no
Age: 0-9 years
Sex: female
Ethnicity/Population group: Hispanic Americans,Causasians
Observation 3:
Clinical Features:
Elevated serum creatine phosphokinase (present) , Ketotic hypoglycemia (present) , Episodic metabolic acidosis (present) , Rhabdomyolysis (present) , Torsade de pointes (present) , Seizures (present) … (more)
Elevated serum creatine phosphokinase (present) , Ketotic hypoglycemia (present) , Episodic metabolic acidosis (present) , Rhabdomyolysis (present) , Torsade de pointes (present) , Seizures (present) , Sensorineural hearing impairment (present) , Intellectual disability (present) , Muscle fiber atrophy (present) , Broad-based gait (present) (less)
Family history: no
Age: 20-29 years
Sex: female
Ethnicity/Population group: Hispanic Americans
Observation 4:
Clinical Features:
Gait ataxia (present) , Intellectual disability (present) , Episodic flaccid weakness (present) , Dysarthria (present) , Elevated serum creatine phosphokinase (present) , Rhabdomyolysis (present) , … (more)
Gait ataxia (present) , Intellectual disability (present) , Episodic flaccid weakness (present) , Dysarthria (present) , Elevated serum creatine phosphokinase (present) , Rhabdomyolysis (present) , Hypothyroidism (present) , Prolonged QTc interval (present) , Cerebellar atrophy (present) , Myopathic facies (present) , Brisk reflexes (present) , Clonus (present) (less)
Family history: no
Age: 10-19 years
Sex: male
Ethnicity/Population group: Hispanic Americans
Observation 5:
Clinical Features:
Intellectual disability (present) , Prolonged QTc interval (present) , Seizures (present) , Acute rhabdomyolysis (present) , Myoglobinuria (present) , Torsade de pointes (present)
Family history: no
Age: 10-19 years
Sex: female
Ethnicity/Population group: Hispanic Americans
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Pathogenic
(Apr 11, 2016)
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criteria provided, single submitter
Method: clinical testing
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Recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome
Affected status: yes
Allele origin:
paternal
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Undiagnosed Diseases Network, NIH
Accession: SCV000622160.1
First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017 |
Comment:
This variant has been described in multiple affected individuals (PMID 26805781)
Clinical Features:
Ventriculomegaly (present) , Short stature (present) , Rhabdomyolysis (present) , Pes planus (present) , Obesity (present) , Macrocytic anemia (present) , Lactic acidosis (present) , … (more)
Ventriculomegaly (present) , Short stature (present) , Rhabdomyolysis (present) , Pes planus (present) , Obesity (present) , Macrocytic anemia (present) , Lactic acidosis (present) , Hypoglycemia (present) , Hypertonia (present) , Hyperammonemia (present) , Global developmental delay (present) , Flexion contracture (present) , Feeding difficulties (present) , Encephalopathy (present) , Elevated serum creatine phosphokinase (present) , Brain atrophy (present) , Abnormality of the palmar creases (present) , Abnormal thalamic MRI signal intensity (present) (less)
Family history: no
Age: 0-9 years
Sex: male
Ethnicity/Population group: Mexican American
Testing laboratory: Baylor Genetics
Date variant was reported to submitter: 2016-04-11
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Pathogenic
(Apr 16, 2020)
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criteria provided, single submitter
Method: clinical testing
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Recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome
Affected status: yes
Allele origin:
inherited
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Department of Molecular and Human Genetics, Baylor College of Medicine
Accession: SCV001334075.1
First in ClinVar: Jul 04, 2020 Last updated: Jul 04, 2020 |
Comment on evidence:
in trans with TANGO2 exons 3-9 deletion
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Likely pathogenic
(May 21, 2021)
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criteria provided, single submitter
Method: curation
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Recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001999936.2
First in ClinVar: Nov 05, 2021 Last updated: Feb 02, 2022 |
Comment:
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, … (more)
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). (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004047293.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
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 … (more)
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. (less)
Clinical Features:
Global developmental delay (present) , Spasticity (present) , Seizure (present) , Microcephaly (present) , Respiratory tract infection (present) , Cerebral palsy (present)
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Pathogenic
(Jan 03, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002215019.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
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). … (more)
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. (less)
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Pathogenic
(May 09, 2019)
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no assertion criteria provided
Method: literature only
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METABOLIC CRISES, RECURRENT, WITH RHABDOMYOLYSIS, CARDIAC ARRHYTHMIAS, AND NEURODEGENERATION
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000266381.3
First in ClinVar: Mar 27, 2016 Last updated: May 13, 2019 |
Comment on evidence:
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), … (more)
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. (less)
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not provided
(-)
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no classification provided
Method: literature only
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Recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV000899268.3
First in ClinVar: May 02, 2019 Last updated: Mar 05, 2024 |
Comment:
Common variant in persons of Hispanic ethnicity from Latin America
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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TANGO2 Deficiency. | Adam MP | - | 2023 | PMID: 29369572 |
CNVs cause autosomal recessive genetic diseases with or without involvement of SNV/indels. | Yuan B | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 32576985 |
Recurrent Muscle Weakness with Rhabdomyolysis, Metabolic Crises, and Cardiac Arrhythmia Due to Bi-allelic TANGO2 Mutations. | Lalani SR | American journal of human genetics | 2016 | PMID: 26805781 |
Text-mined citations for rs752298579 ...
HelpRecord last updated Apr 06, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.