GeneBe

rs397515379

Variant names:

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.Thr172LeufsTer5) 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

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:15O:1

Conservation

PhyloP100: 1.19
Variant links:
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]

Genome browser will be placed here

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

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TTPANM_000370.3 linkc.513_514insTT p.Thr172LeufsTer5 frameshift_variant Exon 3 of 5 ENST00000260116.5 NP_000361.1 P49638

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TTPAENST00000260116.5 linkc.513_514insTT p.Thr172LeufsTer5 frameshift_variant Exon 3 of 5 1 NM_000370.3 ENSP00000260116.4 P49638
TTPAENST00000521138.1 linkn.233-17340_233-17339insTT intron_variant Intron 1 of 1 5

Frequencies

GnomAD3 genomes
AF:
0.0000921
AC:
14
AN:
152066
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000147
AC:
37
AN:
251276
Hom.:
0
AF XY:
0.000184
AC XY:
25
AN XY:
135792
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000299
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.000187
AC:
274
AN:
1461772
Hom.:
0
Cov.:
30
AF XY:
0.000194
AC XY:
141
AN XY:
727194
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.000236
Gnomad4 OTH exome
AF:
0.000132
GnomAD4 genome
AF:
0.0000920
AC:
14
AN:
152184
Hom.:
0
Cov.:
33
AF XY:
0.000121
AC XY:
9
AN XY:
74402
show subpopulations
Gnomad4 AFR
AF:
0.0000482
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000196
Hom.:
0
Bravo
AF:
0.000121
EpiCase
AF:
0.000218
EpiControl
AF:
0.000474

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
May 28, 2019
Mendelics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
GeneReviews
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Dec 17, 2018
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Sep 16, 2020
Natera, Inc.
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Sep 08, 2021
Revvity Omics, Revvity
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 22, 2019
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Jan 03, 2020
Myriad Genetics, Inc.
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Feb 27, 2020
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS4_MOD,PM2. -

Mar 27, 2024
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Pathogenic:5
-
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

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. -

Oct 24, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Jul 01, 2020
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 29, 2024
Athena Diagnostics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

May 02, 2022
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Mar 01, 1996
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Retinal dystrophy Pathogenic:1
Jan 01, 2020
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs397515379; hg19: chr8-63978501; API