8-63072935-C-T

Variant names:

• chr8-63072935-C-T
• rs143010236
• NM_000370.3:c.358G>A

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM5 PP3 PP5_Very_Strong

The NM_000370.3(TTPA):​c.358G>A​(p.Ala120Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000564 in 1,613,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A120delins) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000055 (0 hom.)
• Consequence: TTPA NM_000370.3 missense, splice_region
• Scores: Splicing: ADA: 0.9976
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 U:1 O:1
• Conservation: PhyloP100: 3.55
• Publications: 13 publications found

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]

TTPA Gene-Disease associations (from GenCC):

• familial isolated deficiency of vitamin E

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Myriad Women’s Health, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PM1: In a chain Alpha-tocopherol transfer protein (size 277) in uniprot entity TTPA_HUMAN there are 14 pathogenic changes around while only 2 benign (88%) in NM_000370.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-63066097-GCTA-ACT is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3595815.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 8-63072935-C-T is Pathogenic according to our data. Variant chr8-63072935-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 65591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000370.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTPA	NM_000370.3	MANE Select	c.358G>A	p.Ala120Thr	missense splice_region	Exon 2 of 5	NP_000361.1
	TTPA	NM_001413418.1		c.358G>A	p.Glu120Lys	missense splice_region	Exon 2 of 6	NP_001400347.1
	TTPA	NM_001413416.1		c.358G>A	p.Ala120Thr	missense splice_region	Exon 2 of 5	NP_001400345.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTPA	ENST00000260116.5	TSL:1 MANE Select	c.358G>A	p.Ala120Thr	missense splice_region	Exon 2 of 5	ENSP00000260116.4
	TTPA	ENST00000521138.1	TSL:5	n.232+12883G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152048 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000318 AC: 8 AN: 251236 AF XY: 0.0000221

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000547 AC: 80 AN: 1461834 Hom.: 0 Cov.: 32 AF XY: 0.0000550 AC XY: 40 AN XY: 727220

African (AFR) AF: 0.000149 AC: 5 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000638 AC: 71 AN: 1112002

Other (OTH) AF: 0.0000331 AC: 2 AN: 60390

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152048 Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7 AN XY: 74274

African (AFR) AF: 0.000217 AC: 9 AN: 41406

American (AMR) AF: 0.00 AC: 0 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67996

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000720 Hom.: 0

Bravo AF: 0.0000831

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial isolated deficiency of vitamin E Pathogenic:4 Uncertain:1 Other:1

Nov 14, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Aug 10, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TTPA c.358G>A (p.Ala120Thr) 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 benign effect of the variant on protein function. Due to its location at the last nucleotide of exon adjacent to the canonical splice donor site, several computational tools predict a slight impact on normal splicing: Three predict the variant slightly weakens the adjacent canonical 5' donor site. One predicts the variant has no significant impact on splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 3.2e-05 in 251236 control chromosomes. c.358G>A has been reported in the literature as a mild variant observed in homozygous/compound heterozygous genotype in at-least four individuals affected with mild features of Ataxia With Vitamin E Deficiency (example, Cavalier_1998, Koht_2009, Tabuena_2021). These data indicate that the variant is very likely to be associated with disease. At least three publications report experimental evidence evaluating an impact on protein function demonstrating similar affinity as wild-type for tocopherol and similar ability as wild-type to stimulate intermembrane transfer of tocopherol (example, Morley_2004, Morley_2008). The most pronounced variant effect results in intermediate levels of secretion of Vitamin E from cells (67% of WT), which is interpreted as a marked increase in the rate of degradation of the protein by the proteasome, suggesting that the variant may decrease steady-state levels of the protein (Qian_2006). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Likely pathogenic, n=2; VUS, n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.

Sep 16, 2020

Natera, Inc.

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Mar 10, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 31, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Pathogenic:2

Sep 26, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies show conflicting information about the damaging effect of this variant (PMID: 18458085, 15065857, 16819822); Alters the last nucleotide of the exon and is predicted to destroy the splice donor site and result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown; This variant is associated with the following publications: (PMID: 26740555, 28719003, 20301419, 17576681, 9536098, 24369383, 23077608, Atanasiu2006[Review], 20464573, 21603057, 33197771, 27915290, 26659599, 15065857, 16819822, 25614784, 18458085, 19566498, 9463307, 15300460, 34759169, 30665703, dos Santos2020[Abstract], 37982115)

Aug 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 120 of the TTPA protein (p.Ala120Thr). This variant also falls at the last nucleotide of exon 2, which is part of the consensus splice site for this exon. This variant is present in population databases (rs143010236, gnomAD 0.02%). This missense change has been observed in individuals with ataxia with vitamin E deficiency (PMID: 9463307, 19566498, 34759169). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 65591). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects TTPA function (PMID: 15065857, 16819822, 18458085). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). For these reasons, this variant has been classified as Pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.019	T
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D
Eigen	Benign	0.0069
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	1.6	L
PhyloP100		3.5
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.52
Sift	Uncertain	0.010	D
Sift4G	Benign	0.14	T
Polyphen		0.27	B
Vest4		0.75
MVP		0.94
MPC		0.15
ClinPred		0.29	T
GERP RS		4.9
Varity_R		0.37
gMVP		0.68
Mutation Taster		=60/40	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.60		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.60		Position offset: 0

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

Other links and lift over

dbSNP: rs143010236; hg19: chr8-63985494;