This sequence change creates a premature translational stop signal (p.Glu249Asnfs*15) in the TTPA gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 30 amino acid(s) of the TTPA protein. This variant is present in population databases (rs397515377, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with ataxia with isolated vitamin E deficiency (PMID: 26068213). ClinVar contains an entry for this variant (Variation ID: 9136). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000370.3(TTPA):c.744del (p.Glu249fs)
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.
(11)
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
11
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000370.3(TTPA):c.744del (p.Glu249fs)
Variation ID: 9136 Accession: VCV000009136.23
- Type and length
-
Deletion, 1 bp
- Location
-
Cytogenetic: 8q12.3 8: 63061345 (GRCh38) [ NCBI UCSC ] 8: 63973904 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Apr 4, 2013 Oct 20, 2024 Jul 1, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000370.3:c.744del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000361.1:p.Glu249fs frameshift NM_000370.3:c.744delA MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000370.2:c.744del NM_000370.2:c.744delA NC_000008.11:g.63061346del NC_000008.10:g.63973905del NG_016123.1:g.29709del - Protein change
- E249fs
- Other names
- -
- Canonical SPDI
- NC_000008.11:63061344:TT:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- 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. |
|||
| TTPA | - | - |
GRCh38 GRCh37 |
450 | 477 | |
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 (1) |
no assertion criteria provided
|
Feb 1, 1995 | RCV000009707.2 | |
| Pathogenic (8) |
criteria provided, multiple submitters, no conflicts
|
Mar 1, 2024 | RCV000055806.15 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jul 1, 2024 | RCV001046510.9 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Jan 01, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Familial isolated deficiency of vitamin E
Affected status: yes
Allele origin:
inherited
|
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV000965799.1
First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019 |
|
|
|
Pathogenic
(Dec 13, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Familial isolated deficiency of vitamin E
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002801044.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Jan 22, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001210415.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Glu249Asnfs*15) in the TTPA gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Glu249Asnfs*15) in the TTPA gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 30 amino acid(s) of the TTPA protein. This variant is present in population databases (rs397515377, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with ataxia with isolated vitamin E deficiency (PMID: 26068213). ClinVar contains an entry for this variant (Variation ID: 9136). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Jul 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV005092940.3
First in ClinVar: Aug 04, 2024 Last updated: Oct 20, 2024 |
Comment:
TTPA: PP1:Strong, PM2, PM3, PVS1:Moderate
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Apr 24, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Familial isolated deficiency of vitamin E
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000696612.1
First in ClinVar: Oct 02, 2013 Last updated: Oct 02, 2013 |
Comment:
Variant summary: The TTPA c.744delA (p.Glu249Asnfs) variant results in a premature termination codon, predicted to cause a truncated or absent TTPA protein due to nonsense … (more)
Variant summary: The TTPA c.744delA (p.Glu249Asnfs) variant results in a premature termination codon, predicted to cause a truncated or absent TTPA protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in the large control database ExAC at a frequency of 0.000099 (12/121224 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic TTPA variant (0.0020412). The variant has been reported in over 100 patients of Tunisian and Algerian descent who were homozygous for the variant (Euch-Fayache_2014; Hamza_2015). Addtionally, the variant segregated with disease in several consanguineous families, providing strong evidence of pathogenicity. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
|
|
|
Pathogenic
(Dec 09, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Familial isolated deficiency of vitamin E
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV001194210.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 03, 2020 |
Comment:
NM_000370.3(TTPA):c.744delA(aka E249Nfs*15) is classified as pathogenic in the context of ataxia with vitamin E deficiency. Sources cited for classification include the following: PMID 7719340, 12039660, … (more)
NM_000370.3(TTPA):c.744delA(aka E249Nfs*15) is classified as pathogenic in the context of ataxia with vitamin E deficiency. Sources cited for classification include the following: PMID 7719340, 12039660, 9463307 and 15953402. Classification of NM_000370.3(TTPA):c.744delA(aka E249Nfs*15) is based on the following criteria: The variant causes a premature termination codon that is not expected to be targeted by nonsense-mediated mRNA decay; however, literature evidence strongly supports pathogenicity. Please note: this variant was assessed in the context of healthy population screening. (less)
|
|
|
Pathogenic
(Feb 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial isolated deficiency of vitamin E
Affected status: yes
Allele origin:
unknown
|
3billion
Accession: SCV003841700.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.006%). This variant was predicted to result in … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.006%). This variant was predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10%. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000009136 / PMID: 7719340 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Cerebellar ataxia (present) , Seizure (present) , Reduced tendon reflexes (present) , Impaired proprioception (present) , Arm dystonia (present) , Decreased circulating vitamin E concentration … (more)
Cerebellar ataxia (present) , Seizure (present) , Reduced tendon reflexes (present) , Impaired proprioception (present) , Arm dystonia (present) , Decreased circulating vitamin E concentration (present) (less)
|
|
|
Pathogenic
(Mar 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial isolated deficiency of vitamin E
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004207477.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Ataxia with isolated vitamin E deficiency
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001461508.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
|
Pathogenic
(Feb 01, 1995)
|
no assertion criteria provided
Method: literature only
|
ATAXIA, FRIEDREICH-LIKE, WITH ISOLATED VITAMIN E DEFICIENCY
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000029925.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In 68% of the mutant alleles in 17 families with AVED (277460), Ouahchi et al. (1995) found a deletion of 1 bp (A) at position … (more)
In 68% of the mutant alleles in 17 families with AVED (277460), Ouahchi et al. (1995) found a deletion of 1 bp (A) at position 744. The mutation, referred to as Mediterranean, appeared to have spread in North Africa and Italy. (less)
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Familial isolated deficiency of vitamin E
Affected status: not provided
Allele origin:
unknown
|
GeneReviews
Accession: SCV000086775.2
First in ClinVar: Oct 02, 2013 Last updated: Oct 01, 2022 |
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
TTPA: PP1:Strong, PM2, PM3, PVS1:Moderate
Comment:
Variant summary: The TTPA c.744delA (p.Glu249Asnfs) variant results in a premature termination codon, predicted to cause a truncated or absent TTPA protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in the large control database ExAC at a frequency of 0.000099 (12/121224 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic TTPA variant (0.0020412). The variant has been reported in over 100 patients of Tunisian and Algerian descent who were homozygous for the variant (Euch-Fayache_2014; Hamza_2015). Addtionally, the variant segregated with disease in several consanguineous families, providing strong evidence of pathogenicity. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Comment:
NM_000370.3(TTPA):c.744delA(aka E249Nfs*15) is classified as pathogenic in the context of ataxia with vitamin E deficiency. Sources cited for classification include the following: PMID 7719340, 12039660, 9463307 and 15953402. Classification of NM_000370.3(TTPA):c.744delA(aka E249Nfs*15) is based on the following criteria: The variant causes a premature termination codon that is not expected to be targeted by nonsense-mediated mRNA decay; however, literature evidence strongly supports pathogenicity. Please note: this variant was assessed in the context of healthy population screening.
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.006%). This variant was predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10%. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000009136 / PMID: 7719340 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
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:
This sequence change creates a premature translational stop signal (p.Glu249Asnfs*15) in the TTPA gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 30 amino acid(s) of the TTPA protein. This variant is present in population databases (rs397515377, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with ataxia with isolated vitamin E deficiency (PMID: 26068213). ClinVar contains an entry for this variant (Variation ID: 9136). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Comment:
TTPA: PP1:Strong, PM2, PM3, PVS1:Moderate
Comment:
Variant summary: The TTPA c.744delA (p.Glu249Asnfs) variant results in a premature termination codon, predicted to cause a truncated or absent TTPA protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in the large control database ExAC at a frequency of 0.000099 (12/121224 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic TTPA variant (0.0020412). The variant has been reported in over 100 patients of Tunisian and Algerian descent who were homozygous for the variant (Euch-Fayache_2014; Hamza_2015). Addtionally, the variant segregated with disease in several consanguineous families, providing strong evidence of pathogenicity. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Comment:
NM_000370.3(TTPA):c.744delA(aka E249Nfs*15) is classified as pathogenic in the context of ataxia with vitamin E deficiency. Sources cited for classification include the following: PMID 7719340, 12039660, 9463307 and 15953402. Classification of NM_000370.3(TTPA):c.744delA(aka E249Nfs*15) is based on the following criteria: The variant causes a premature termination codon that is not expected to be targeted by nonsense-mediated mRNA decay; however, literature evidence strongly supports pathogenicity. Please note: this variant was assessed in the context of healthy population screening.
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.006%). This variant was predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10%. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000009136 / PMID: 7719340 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Ataxia with Vitamin E Deficiency. | Adam MP | - | 2023 | PMID: 20301419 |
| Molecular and clinical study of a cohort of 110 Algerian patients with autosomal recessive ataxia. | Hamza W | BMC medical genetics | 2015 | PMID: 26068213 |
| Molecular, clinical and peripheral neuropathy study of Tunisian patients with ataxia with vitamin E deficiency. | El Euch-Fayache G | Brain : a journal of neurology | 2014 | PMID: 24369383 |
| Vitamin E deficiency ataxia with (744 del A) mutation on alpha-TTP gene: genetic and clinical peculiarities in Moroccan patients. | Marzouki N | European journal of medical genetics | 2005 | PMID: 15953402 |
| Clinical comparison between AVED patients with 744 del A mutation and Friedreich ataxia with GAA expansion in 15 Moroccan families. | Benomar A | Journal of the neurological sciences | 2002 | PMID: 12039660 |
| Ataxia with isolated vitamin E deficiency: heterogeneity of mutations and phenotypic variability in a large number of families. | Cavalier L | American journal of human genetics | 1998 | PMID: 9463307 |
| Ataxia with isolated vitamin E deficiency is caused by mutations in the alpha-tocopherol transfer protein. | Ouahchi K | Nature genetics | 1995 | PMID: 7719340 |
Text-mined citations for rs397515377 ...
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 Oct 20, 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.