rs121917850
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5
The NM_000370.3(TTPA):c.575G>A(p.Arg192His) variant causes a missense change. The variant allele was found at a frequency of 0.0000806 in 1,612,170 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R192C) has been classified as Uncertain significance.
Frequency
Consequence
NM_000370.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TTPA | NM_000370.3 | c.575G>A | p.Arg192His | missense_variant | 4/5 | ENST00000260116.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTPA | ENST00000260116.5 | c.575G>A | p.Arg192His | missense_variant | 4/5 | 1 | NM_000370.3 | P1 | |
TTPA | ENST00000521138.1 | n.233-15691G>A | intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000105 AC: 16AN: 151914Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000559 AC: 14AN: 250298Hom.: 0 AF XY: 0.0000739 AC XY: 10AN XY: 135296
GnomAD4 exome AF: 0.0000781 AC: 114AN: 1460256Hom.: 0 Cov.: 30 AF XY: 0.0000743 AC XY: 54AN XY: 726458
GnomAD4 genome ? AF: 0.000105 AC: 16AN: 151914Hom.: 0 Cov.: 33 AF XY: 0.000135 AC XY: 10AN XY: 74186
ClinVar
Submissions by phenotype
Familial isolated deficiency of vitamin E Pathogenic:2Other:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Apr 27, 2019 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 08, 2024 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Oct 14, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 17, 2022 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 192 of the TTPA protein (p.Arg192His). This variant is present in population databases (rs121917850, gnomAD 0.01%). This missense change has been observed in individual(s) with ataxia with isolated vitamin E deficiency (PMID: 9463307). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 9140). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TTPA protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TTPA function (PMID: 15065857, 18458085, 21110980). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Ataxia, Friedreich-like, with isolated vitamin E deficiency Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 1996 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 28, 2023 | Variant summary: TTPA c.575G>A (p.Arg192His) results in a non-conservative amino acid change located in the CRAL-TRIO lipid binding domain (IPR001251) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 250298 control chromosomes (gnomAD). This frequency is not higher than the estimated maximum expected for a pathogenic variant in TTPA causing Ataxia with Vitamin E Deficiency (0.002), allowing no conclusion about variant significance. c.575G>A has been reported in the literature in three siblings affected with a milder phenotype of Ataxia with Vitamin E Deficiency, who carried a pathogenic variant in trans (Hentati_1996, Cavalier_1998). These data indicate that the variant may be associated with disease. Publications reporting experimental evidence evaluating an impact on protein function showed no apparent effect of the variant on in vitro transfer activity (Morley_2004, Morley_2008, Zhang_2011), and no change in intracellular localization (Chung_2016). Inferred from the crystal structure, the Arg192 amino acid side-chain participates in the formation of a positively charged cleft required for phosphatidylinositol phosphates (PIPs) binding, and a different missense (R59W) affecting a residue also involved in the formation of this pocket, was demonstrated to result in loss of PIPs binding ability, and was not able to stimulate alpha-tocopherol secretion in hepatoma cells, although it didn't affect in vitro transfer activity (Kono_2013). Three submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=2) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
TTPA-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 28, 2023 | The TTPA c.575G>A variant is predicted to result in the amino acid substitution p.Arg192His. This variant was reported in the compound heterozygous state in an individual with ataxia with vitamin E deficiency (Hentati et al. 1996. PubMed ID: 8602747). This variant is reported in 0.010% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/8-63976853-C-T). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at