rs397515379
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000370.3(TTPA):c.513_514insTT(p.Thr172fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000178 in 1,613,956 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000092 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00019 ( 0 hom. )
Consequence
TTPA
NM_000370.3 frameshift
NM_000370.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.19
Genes affected
TTPA (HGNC:12404): (alpha tocopherol transfer protein) This gene encodes a soluble protein that binds alpha-trocopherol, a form of vitamin E, with high selectivity and affinity. This protein plays an important role in regulating vitamin E levels in the body by transporting vitamin E between membrane vesicles and facilitating the secretion of vitamin E from hepatocytes to circulating lipoproteins. Mutations in this gene cause hereditary vitamin E deficiency (ataxia with vitamin E deficiency, AVED) and retinitis pigmentosa. [provided by RefSeq, Nov 2009]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 8-63065942-T-TAA is Pathogenic according to our data. Variant chr8-63065942-T-TAA is described in ClinVar as [Pathogenic]. Clinvar id is 9139.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Ensembl
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GnomAD3 genomes 0.0000921 AC: 14AN: 152066Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000147 AC: 37AN: 251276Hom.: 0 AF XY: 0.000184 AC XY: 25AN XY: 135792
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GnomAD4 exome AF: 0.000187 AC: 274AN: 1461772Hom.: 0 Cov.: 30 AF XY: 0.000194 AC XY: 141AN XY: 727194
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GnomAD4 genome 0.0000920 AC: 14AN: 152184Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9AN XY: 74402
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:15Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial isolated deficiency of vitamin E Pathogenic:8Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 17, 2018 | The p.Thr172LeufsX5 variant in TTPA has been reported in at least 3 homozygous a nd 3 compound heterozygous individuals with ataxia and vitamin E deficiency (Oua hchi 1995, Hentati 1996, Cavalier 1998, Rossato 2014, Elkamil 2015). It has also been identified in 0.03% (38/129082) of European chromosomes by gnomAD (http:// gnomad.broadinstitute.org). However, this frequency is low enough to be consiste nt with a recessive carrier frequency. This variant has also been reported in Cl inVar (Variation ID #9139). This variant is predicted to cause a frameshift, whi ch alters the protein?s amino acid sequence beginning at position 172 and leads to a premature termination codon 5 amino acids downstream. This alteration is th en predicted to lead to a truncated or absent protein. Biallelic loss of functio n of the TTPA gene is an established disease mechanism in autosomal recessive at axia with vitamin E deficiency. In summary, this variant meets criteria to be cl assified as pathogenic for autosomal recessive ataxia with vitamin E deficiency. ACMG/AMP Criteria applied: PVS1, PM3_Strong, PM2_Supporting. - |
| not provided, no classification provided | literature only | GeneReviews | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 22, 2019 | Variant summary: TTPA c.513_514insTT (p.Thr172LeufsX5) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00015 in 251276 control chromosomes (gnomAD). This frequency is not higher than the expected maximum for a pathogenic variant in TTPA causing Ataxia with Vitamin E Deficiency (0.00015 vs 0.002). c.513_514insTT has been reported in the literature in multiple homozygous- and compound heterozygote individuals affected with 'Ataxia with Vitamin E Deficiency' (e.g. Mariotti_2004). These data indicate that the variant is very likely to be associated with disease. A ClinVar submission (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 27, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Feb 27, 2020 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS4_MOD,PM2. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jan 03, 2020 | NM_000370.3(TTPA):c.513_514insTT(T172Lfs*5) is classified as pathogenic in the context of ataxia with vitamin E deficiency. Sources cited for classification include the following: PMID 9463307 and 15300460. Classification of NM_000370.3(TTPA):c.513_514insTT(T172Lfs*5) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 08, 2021 | - - |
not provided Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Mar 29, 2024 | This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity. (http://gnomad.broadinstitute.org) This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2020 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The TTPA p.T172Lfs*5 variant was identified in >15 patients with ataxia with vitamin E deficiency as a homozygous or compound heterozygous variant (Mariotti_2004_PMID:15300460; Elkamil_2005_PMID:25614784; Angelini_2002_PMID:12112220; Schuekle_2000_PMID:11013295; Cavalier_1998_PMID:9463307; Rossato_2014_PMID:23445347; Martinello_1998_PMID:9588854; Hentati_1996_PMID:8602747). The variant was identified in dbSNP (ID: rs397515379) and ClinVar (classified as pathogenic by Athena Diagnostics, Laboratory for Molecular Medicine, Counsyl and Mendelics). The variant was identified in control databases in 41 of 282676 chromosomes at a frequency of 0.000145 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 38 of 129082 chromosomes (freq: 0.000294), Other in 1 of 7218 chromosomes (freq: 0.000139), South Asian in 1 of 30600 chromosomes (freq: 0.000033) and Latino in 1 of 35388 chromosomes (freq: 0.000028), but was not observed in the African, Ashkenazi Jewish, East Asian, or European (Finnish) populations. The c.513_514insTT variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 172 and leads to a premature stop codon 5 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the TTPA gene are an established mechanism of disease in ataxia with vitamin E deficiency and are the type of variants expected to cause the disorder when foudn in the homozygous or compound heterozygous state. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 02, 2024 | This sequence change creates a premature translational stop signal (p.Thr172Leufs*5) in the TTPA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TTPA are known to be pathogenic (PMID: 9463307, 26068213). This variant is present in population databases (rs397515379, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with ataxia with isolated vitamin E deficiency (PMID: 9463307, 9588854, 11013295, 12112220, 12470185, 15300460, 23445347). ClinVar contains an entry for this variant (Variation ID: 9139). 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 02, 2022 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 7719340, 9463307, 8602747, 23445347, 31980526, 31589614, 32928973, 25614784) - |
Ataxia, Friedreich-like, with isolated vitamin E deficiency Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 1996 | - - |
Retinal dystrophy Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg | Jan 01, 2020 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at