rs121917850

chr8-63064294-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

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:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000078 (0 hom.)
• Consequence: TTPA NM_000370.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:4 O:1
• Conservation: PhyloP100: 5.63

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a chain Alpha-tocopherol transfer protein (size 277) in uniprot entity TTPA_HUMAN there are 18 pathogenic changes around while only 3 benign (86%) in NM_000370.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.865
• PP5: Variant 8-63064294-C-T is Pathogenic according to our data. Variant chr8-63064294-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 9140.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=4, Likely_pathogenic=2, not_provided=1}. Variant chr8-63064294-C-T is described in Lovd as [Likely_pathogenic].

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: 16 AN: 151914 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

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: 0.000177

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000559 AC: 14 AN: 250298 Hom.: 0 AF XY: 0.0000739 AC XY: 10 AN XY: 135296

Gnomad AFR exome AF: 0.0000619

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000656

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000796

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000781 AC: 114 AN: 1460256 Hom.: 0 Cov.: 30 AF XY: 0.0000743 AC XY: 54 AN XY: 726458

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000506

Gnomad4 SAS exome AF: 0.0000697

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000909

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.000105 AC: 16 AN: 151914 Hom.: 0 Cov.: 33 AF XY: 0.000135 AC XY: 10 AN XY: 74186

Gnomad4 AFR AF: 0.0000725

Gnomad4 AMR AF: 0.0000657

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000177

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000191 Hom.: 0

Bravo AF: 0.0000718

ExAC AF: 0.0000906 AC: 11

EpiCase AF: 0.0000545

EpiControl AF: 0.0000594

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:4 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial isolated deficiency of vitamin E Pathogenic:2 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 03, 2023	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Apr 27, 2019	- -

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.16
Cadd	Pathogenic	30
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.80	D
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.047	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	-0.0036	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-3.2	D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.19	T
Polyphen		1.0	D
Vest4		0.93
MVP		0.95
MPC		0.64
ClinPred		0.46	T
GERP RS		5.7
Varity_R		0.70
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs121917850; hg19: chr8-63976853;