rs35916840

chr8-63064208-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3 PP5

The NM_000370.3(TTPA):c.661C>T(p.Arg221Trp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000286 in 1,606,650 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: TTPA NM_000370.3 missense, splice_region
• Scores: Splicing: ADA: 0.9906
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:2 O:1
• Conservation: PhyloP100: 4.05

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 6 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: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 8-63064208-G-A is Pathogenic according to our data. Variant chr8-63064208-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 65597.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, not_provided=1, Uncertain_significance=2, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTPA	NM_000370.3	c.661C>T	p.Arg221Trp	missense_variant, splice_region_variant	4/5	ENST00000260116.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTPA	ENST00000260116.5	c.661C>T	p.Arg221Trp	missense_variant, splice_region_variant	4/5	1	NM_000370.3	P1
TTPA	ENST00000521138.1	n.233-15605C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 151958 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000201 AC: 5 AN: 249258 Hom.: 0 AF XY: 0.0000223 AC XY: 3 AN XY: 134676

Gnomad AFR exome AF: 0.0000622

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000330

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000267

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000289 AC: 42 AN: 1454692 Hom.: 0 Cov.: 30 AF XY: 0.0000276 AC XY: 20 AN XY: 724010

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000344

Gnomad4 OTH exome AF: 0.0000499

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 151958 Hom.: 0 Cov.: 33 AF XY: 0.0000270 AC XY: 2 AN XY: 74208

Gnomad4 AFR AF: 0.0000725

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000107 Hom.: 0

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000546

EpiControl AF: 0.0000596

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	May 23, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 07, 2022	Variant summary: TTPA c.661C>T (p.Arg221Trp) results in a non-conservative amino acid change located in the CRAL-TRIO lipid binding domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 249258 control chromosomes. c.661C>T has been reported in the literature in at least three homozygous individuals with Ataxia With Vitamin E Deficiency and is reported in association with severe phenotype (Cavalier_1998, Shakya_2019). Functional studies have shown the variant to impair the ability of TTP to facilitate the secretion of vitamin E from cells and imparts a marked instability on the TTP protein (Qian_2006). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 10, 2023	- -

not provided Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jul 31, 2022	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 221 of the TTPA protein (p.Arg221Trp). This variant is present in population databases (rs35916840, gnomAD 0.01%). This missense change has been observed in individual(s) with ataxia with isolated vitamin E deficiency (PMID: 9463307, 31429931). ClinVar contains an entry for this variant (Variation ID: 65597). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects TTPA function (PMID: 15065857). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 08, 2017	The R221W variant in the TTPA gene has been reported previously in the homozygous state in several related individuals with ataxia and vitamin E deficiency (AVED); one individual also had cardiomyopathy (Cavalier et al., 1998). The R221W variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R221W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs in a residue critical for phosphatidylinositol lipid binding, at a position that is conserved across species. Functional studies demonstrate the R221W variant caused marked instability of the TTPA protein which has impaired ability to facilitate transport of tocopherol out of the lysosomes (Qian et al., 2006). We interpret R221W as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.39
Cadd	Pathogenic	30
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	3.8	H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-6.7	D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.94
MVP		0.97
MPC		0.66
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.96
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.73
SpliceAI score (max)		0.010		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: rs35916840; hg19: chr8-63976767; COSMIC: COSV52646163;