ClinVar Genomic variation as it relates to human health
NM_000116.5(TAFAZZIN):c.589G>A (p.Gly197Arg)
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_000116.5(TAFAZZIN):c.589G>A (p.Gly197Arg)
Variation ID: 11105 Accession: VCV000011105.10
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq28 X: 154420037 (GRCh38) [ NCBI UCSC ] X: 153648376 (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 Jul 15, 2018 Apr 15, 2024 Sep 1, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000116.5:c.589G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000107.1:p.Gly197Arg missense NM_000116.4:c.589G>A NM_001303465.2:c.601G>A NP_001290394.1:p.Gly201Arg missense NM_181311.4:c.499G>A NP_851828.1:p.Gly167Arg missense NM_181312.4:c.547G>A NP_851829.1:p.Gly183Arg missense NM_181313.4:c.457G>A NP_851830.1:p.Gly153Arg missense NR_024048.3:n.910G>A non-coding transcript variant NC_000023.11:g.154420037G>A NC_000023.10:g.153648376G>A NG_009634.2:g.13503G>A LRG_131:g.13503G>A LRG_131t1:c.589G>A LRG_131p1:p.Gly197Arg Q16635:p.Gly197Arg - Protein change
- G197R, G153R, G201R, G183R, G167R
- Other names
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- Canonical SPDI
- NC_000023.11:154420036: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
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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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
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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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TAFAZZIN | - | - |
GRCh38 GRCh37 |
407 | 708 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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 (3) |
criteria provided, multiple submitters, no conflicts
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Oct 20, 2020 | RCV000011854.17 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 1, 2023 | RCV003226156.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 1, 2023 | RCV003333950.5 |
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
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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
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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
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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
(Mar 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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TAFAZZIN-Related Disorders
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003922508.1
First in ClinVar: May 13, 2023 Last updated: May 13, 2023 |
Comment:
Variant summary: TAZ c.589G>A (p.Gly197Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: TAZ c.589G>A (p.Gly197Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183500 control chromosomes (gnomAD). c.589G>A has been reported in the literature in multiple individuals affected with Barth Syndrome (e.g. D'Adamo_1997, Bleyl_1997, Cantlay_1999, Ruggolotto_2003, Donati_2006, Alharbi_2022). These data indicate that the variant is very likely to be associated with disease. One clinical diagnostic laboratory has submitted a clinical-significance assessment for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Sep 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004042406.5
First in ClinVar: Oct 14, 2023 Last updated: Apr 15, 2024 |
Comment:
TAFAZZIN: PP1:Strong, PM2, PM5, PS4:Moderate, PP3
Number of individuals with the variant: 1
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Pathogenic
(Oct 20, 2020)
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criteria provided, single submitter
Method: clinical testing
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3-Methylglutaconic aciduria type 2
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001585907.1
First in ClinVar: May 10, 2021 Last updated: May 10, 2021 |
Comment:
This sequence change replaces glycine with arginine at codon 197 of the TAZ protein (p.Gly197Arg). The glycine residue is highly conserved and there is a … (more)
This sequence change replaces glycine with arginine at codon 197 of the TAZ protein (p.Gly197Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be hemizygous in several individuals affected with Barth syndrome (PMID: 9382096, 14654353). This variant is also known as G877A in the literature. ClinVar contains an entry for this variant (Variation ID: 11105). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Not Available; PolyPhen-2: Probably Damaging; Align-GVGD: Not Available). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jul 21, 2020)
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criteria provided, single submitter
Method: clinical testing
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3-Methylglutaconic aciduria type 2
(X-linked inheritance)
Affected status: no, yes
Allele origin:
maternal,
unknown
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Molecular Diagnostics Lab, Nemours Children's Health, Delaware
Accession: SCV003935935.1
First in ClinVar: Jul 01, 2023 Last updated: Jul 01, 2023 |
Observation 1:
Age: 20-29 years
Sex: male
Tissue: blood
Observation 2:
Age: 10-19 years
Sex: male
Tissue: blood
Observation 3:
Age: 10-19 years
Sex: male
Tissue: blood
Observation 4:
Age: 0-9 years
Sex: male
Tissue: blood
Observation 5:
Sex: female
Tissue: blood
Observation 6:
Age: 10-19 years
Sex: male
Tissue: blood
Observation 7:
Sex: male
Tissue: blood
Observation 8:
Age: 0-9 years
Sex: male
Tissue: blood
Observation 9:
Age: 10-19 years
Sex: female
Tissue: blood
Observation 10:
Sex: female
Tissue: blood
Observation 11:
Sex: female
Tissue: blood
Observation 12:
Sex: female
Tissue: blood
Observation 13:
Sex: male
Tissue: amniocytes
Observation 14:
Sex: male
Tissue: amniocytes
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Pathogenic
(Oct 01, 2010)
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no assertion criteria provided
Method: literature only
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BARTH SYNDROME
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000032087.4
First in ClinVar: Apr 04, 2013 Last updated: Mar 28, 2022 |
Comment on evidence:
In a Utah family, Bleyl et al. (1997) observed 6 males with neonatal onset of left ventricular failure and arrhythmias associated with the pathognomonic echocardiographic … (more)
In a Utah family, Bleyl et al. (1997) observed 6 males with neonatal onset of left ventricular failure and arrhythmias associated with the pathognomonic echocardiographic findings of isolated left ventricular noncompaction (LVNC). Neutropenia was seen in 2 patients, and another patient had muscle weakness. Genetic linkage analysis localized the causative gene to Xq28. Bleyl et al. (1997) screened the G4.5 gene with SSCP and direct sequencing revealed a G-A transition in exon 8, resulting in a gly197-to-arg (G197R) substitution at a highly conserved residue. The mutation segregated with LVNC in the family and was not found in 300 unrelated females. In a male infant who died of Barth syndrome (BTHS; 302060) at 14 months of age, D'Adamo et al. (1997) identified the G197R mutation in the G4.5 gene. The patient exhibited dilated cardiomyopathy, neutropenia, and 3-methylglutaconic aciduria. In a boy with Barth syndrome, previously studied at 6.5 years of age by Christodoulou et al. (1994), Johnston et al. (1997) identified the 877G-A transition exon 8 of the G4.5 gene, resulting in the G197R substitution. The patient presented at 3 months of age with congestive heart failure, and had recurrent episodes of neutropenia. At 6.5 years of age, his height, weight, and head circumference were all below the 3rd centile, and he had a myopathic facial appearance and a nasal quality to his speech. Echocardiography showed moderate cardiac enlargement with left ventricular dilation but no outflow obstruction. Muscle bulk, power, and tone were decreased and he had a waddling gait. In 2 families with Barth syndrome, Cantlay et al. (1999) identified the G197R mutation in the G4.5 gene. One family presented a history of 5 boys over 2 generations who died from cardiomyopathy between 4 to 6 months of age. The mutation was detected in the proband's unaffected sister, mother, and a maternal aunt. In the other family, the proband presented at 6 months of age with dilated cardiomyopathy and was found to have failure to thrive, skeletal myopathy, intermittent neutropenia and elevated urinary 3-methylglutaconic acid. He underwent cardiac transplantation at 11 months of age, and died at age 7 years of T-cell non-Hodgkin lymphoma. His mother and maternal grandmother also carried the mutation. Steward et al. (2010) studied a distant branch of the latter family, in which a known carrier of the G197R mutation gave birth to a male infant who died at 1 week of age due to cardiac decompensation triggered by ventricular arrhythmias. Disease expression in this family was variable: a cousin with BTHS was well until he fell behind on motor milestones at 1 year of age, developed feeding problems and lethargy at 2.5 years, was diagnosed with CMD at 3.5 years, and required cardiac transplantation several months later. Another cousin was only diagnosed with BTHS after the disease was identified in his younger brother, who developed CMD at 3 months of age, without neutropenia; when diagnosed at 3.5 years of age, the older brother's only sign was proximal myopathy. In 2 brothers with Barth syndrome and their affected cousin, and another unrelated BTHS patient, Hastings et al. (2009) identified the G197R mutation in the TAZ gene. The 4 patients exhibited a characteristic facial appearance that was most evident in infancy and included a tall and broad forehead, round face with prominent chin and full cheeks, large ears, and deep-set eyes. (less)
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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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Fine-Tuning 3-Methylglutaconic Aciduria Cutoffs for a Patient with Infantile-Onset Barth Syndrome. | Alharbi H | Clinical chemistry | 2022 | PMID: 35104856 |
Barth syndrome: an X-linked cause of fetal cardiomyopathy and stillbirth. | Steward CG | Prenatal diagnosis | 2010 | PMID: 20812380 |
Dysmorphology of Barth syndrome. | Hastings R | Clinical dysmorphology | 2009 | PMID: 19648820 |
Barth syndrome presenting with acute metabolic decompensation in the neonatal period. | Donati MA | Journal of inherited metabolic disease | 2006 | PMID: 16906470 |
Long-term treatment of Barth syndrome with pantothenic acid: a retrospective study. | Rugolotto S | Molecular genetics and metabolism | 2003 | PMID: 14654353 |
Genetic analysis of the G4.5 gene in families with suspected Barth syndrome. | Cantlay AM | The Journal of pediatrics | 1999 | PMID: 10484795 |
Neonatal, lethal noncompaction of the left ventricular myocardium is allelic with Barth syndrome. | Bleyl SB | American journal of human genetics | 1997 | PMID: 9382097 |
The X-linked gene G4.5 is responsible for different infantile dilated cardiomyopathies. | D'Adamo P | American journal of human genetics | 1997 | PMID: 9382096 |
Mutation characterization and genotype-phenotype correlation in Barth syndrome. | Johnston J | American journal of human genetics | 1997 | PMID: 9345098 |
Xq28-linked noncompaction of the left ventricular myocardium: prenatal diagnosis and pathologic analysis of affected individuals. | Bleyl SB | American journal of medical genetics | 1997 | PMID: 9332651 |
Barth syndrome: clinical observations and genetic linkage studies. | Christodoulou J | American journal of medical genetics | 1994 | PMID: 8042670 |
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Text-mined citations for rs132630277 ...
HelpRecord last updated Apr 15, 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.