In silico analysis supports that this missense variant has a deleterious effect on splicing; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25941633, 24887148, 16880272, 25525159, 9382096, 14764526, 23656970, 23361305, 21932011, 29249525, 29447731, 30369941, 32183154, 32600061, 33049752)
ClinVar Genomic variation as it relates to human health
NM_000116.5(TAFAZZIN):c.646G>A (p.Gly216Arg)
Germline
Classification
Help
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.
(5)
Help
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.
Pathogenic/Likely pathogenic
5
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000116.5(TAFAZZIN):c.646G>A (p.Gly216Arg)
Variation ID: 426783 Accession: VCV000426783.8
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq28 X: 154420094 (GRCh38) [ NCBI UCSC ] X: 153648433 (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 May 22, 2017 Feb 14, 2024 Apr 12, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000116.5:c.646G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000107.1:p.Gly216Arg missense NM_001303465.2:c.658G>A NP_001290394.1:p.Gly220Arg missense NM_181311.4:c.556G>A NP_851828.1:p.Gly186Arg missense NM_181312.4:c.604G>A NP_851829.1:p.Gly202Arg missense NM_181313.4:c.514G>A NP_851830.1:p.Gly172Arg missense NR_024048.3:n.967G>A non-coding transcript variant NC_000023.11:g.154420094G>A NC_000023.10:g.153648433G>A NG_009634.2:g.13560G>A LRG_131:g.13560G>A LRG_131t1:c.646G>A LRG_131p1:p.Gly216Arg - Protein change
- G216R, G172R, G186R, G202R, G220R
- Other names
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- Canonical SPDI
- NC_000023.11:154420093: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.
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- Links
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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
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. |
|||
| TAFAZZIN | - | - |
GRCh38 GRCh37 |
412 | 720 | |
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. |
|---|---|---|---|---|
| Pathogenic (3) |
criteria provided, single submitter
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Apr 12, 2023 | RCV000489828.5 | |
| Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Feb 14, 2023 | RCV000816124.4 |
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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|---|---|---|---|---|---|
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Pathogenic
(Apr 12, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000577316.4
First in ClinVar: May 22, 2017 Last updated: Apr 23, 2023 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on splicing; Not observed at significant frequency in large population cohorts (gnomAD); This … (more)
In silico analysis supports that this missense variant has a deleterious effect on splicing; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25941633, 24887148, 16880272, 25525159, 9382096, 14764526, 23656970, 23361305, 21932011, 29249525, 29447731, 30369941, 32183154, 32600061, 33049752) (less)
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Pathogenic
(Feb 14, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
3-Methylglutaconic aciduria type 2
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000956616.2
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic … (more)
For these reasons, this variant has been classified as Pathogenic. This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 216 of the TAZ protein (p.Gly216Arg). This variant also falls at the last nucleotide of exon 8, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Barth syndrome (PMID: 9382096, 21932011, 23361305, 23656970, 24887148). ClinVar contains an entry for this variant (Variation ID: 426783). 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 TAZ function (PMID: 16880272). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. (less)
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Likely pathogenic
(Jul 20, 2020)
|
criteria provided, single submitter
Method: clinical testing
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3-Methylglutaconic aciduria type 2
(X-linked inheritance)
Affected status: yes, no
Allele origin:
maternal,
unknown
|
Molecular Diagnostics Lab, Nemours Children's Health, Delaware
Accession: SCV003935893.1
First in ClinVar: Jul 01, 2023 Last updated: Jul 01, 2023 |
Observation 1:
Age: 0-9 years
Sex: male
Tissue: blood
Observation 2:
Age: 20-29 years
Sex: female
Tissue: blood
Observation 3:
Age: 0-9 years
Sex: male
Tissue: blood
Observation 4:
Age: 30-39 years
Sex: female
Tissue: blood
Observation 5:
Age: 50-59 years
Sex: female
Tissue: blood
|
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001953268.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001966008.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
|
Comment:
Comment:
For these reasons, this variant has been classified as Pathogenic. This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 216 of the TAZ protein (p.Gly216Arg). This variant also falls at the last nucleotide of exon 8, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Barth syndrome (PMID: 9382096, 21932011, 23361305, 23656970, 24887148). ClinVar contains an entry for this variant (Variation ID: 426783). 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 TAZ function (PMID: 16880272). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site.
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. |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on splicing; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25941633, 24887148, 16880272, 25525159, 9382096, 14764526, 23656970, 23361305, 21932011, 29249525, 29447731, 30369941, 32183154, 32600061, 33049752)
Comment:
For these reasons, this variant has been classified as Pathogenic. This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 216 of the TAZ protein (p.Gly216Arg). This variant also falls at the last nucleotide of exon 8, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Barth syndrome (PMID: 9382096, 21932011, 23361305, 23656970, 24887148). ClinVar contains an entry for this variant (Variation ID: 426783). 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 TAZ function (PMID: 16880272). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Clinical and Echocardiographic Impact of Tafazzin Variants on Dilated Cardiomyopathy Phenotype in Left Ventricular Non-Compaction Patients in Early Infancy. | Hirono K | Circulation journal : official journal of the Japanese Circulation Society | 2018 | PMID: 30122738 |
| Cardiomyopathy in a male patient with neutropenia and growth delay. | Folsi V | Italian journal of pediatrics | 2014 | PMID: 24887148 |
| Natural history of Barth syndrome: a national cohort study of 22 patients. | Rigaud C | Orphanet journal of rare diseases | 2013 | PMID: 23656970 |
| Left ventricular noncompaction (LVNC) and low mitochondrial membrane potential are specific for Barth syndrome. | Karkucinska-Wieckowska A | Journal of inherited metabolic disease | 2013 | PMID: 23361305 |
| Barth syndrome diagnosed in the subclinical stage of heart failure based on the presence of lipid storage myopathy and isolated noncompaction of the ventricular myocardium. | Takeda A | European journal of pediatrics | 2011 | PMID: 21932011 |
| Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
| Mitochondrial mislocalization and altered assembly of a cluster of Barth syndrome mutant tafazzins. | Claypool SM | The Journal of cell biology | 2006 | PMID: 16880272 |
| Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
| The X-linked gene G4.5 is responsible for different infantile dilated cardiomyopathies. | D'Adamo P | American journal of human genetics | 1997 | PMID: 9382096 |
Text-mined citations for rs1085307797 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 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.