NM_000370.3(TTPA):c.513_514insTT (p.Thr172fs) AND Familial isolated deficiency of vitamin E

Germline classification:: Pathogenic (9 submissions)
Last evaluated:: Mar 27, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000055800.23

Allele description [Variation Report for NM_000370.3(TTPA):c.513_514insTT (p.Thr172fs)]

NM_000370.3(TTPA):c.513_514insTT (p.Thr172fs)

Gene:

TTPA:alpha tocopherol transfer protein [Gene - OMIM - HGNC]

Variant type:

Insertion

Cytogenetic location:

8q12.3

Genomic location:

Preferred name:

NM_000370.3(TTPA):c.513_514insTT (p.Thr172fs)

HGVS:

NC_000008.11:g.63065942_63065943insAA
NG_016123.1:g.25111_25112insTT
NM_000370.3:c.513_514insTTMANE SELECT
NP_000361.1:p.Thr172fs
NC_000008.10:g.63978501_63978502insAA
NM_000370.2:c.513_514insTT
p.Thr172LeufsX5

Protein change:

T172fs

Links:

OMIM: 600415.0004; dbSNP: rs397515379

NCBI 1000 Genomes Browser:

rs397515379

Molecular consequence:

NM_000370.3:c.513_514insTT - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

Condition(s)

Name:: Familial isolated deficiency of vitamin E (AVED)
Synonyms:: Ataxia with vitamin E deficiency; Ataxia with isolated vitamin E deficiency; Friedreich-like ataxia with selective vitamin E deficiency
Identifiers:: MONDO: MONDO:0010188; MedGen: C1848533; Orphanet: 96; OMIM: 277460

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000086769	GeneReviews	no classification provided	not provided	unknown	literature only	PubMed (1) [See all records that cite this PMID]
SCV000967687	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Dec 17, 2018)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 23445347, 7719340, 8602747, 9463307, 25614784, 24033266
SCV001137639	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Pathogenic (May 28, 2019)	unknown	clinical testing	Citation Link,
SCV001194120	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019))	Pathogenic (Jan 3, 2020)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 9463307, 15300460 Citation Link,
SCV001363570	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Nov 22, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001367372	Centre for Mendelian Genomics, University Medical Centre Ljubljana	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 27, 2020)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001461510	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV002022475	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 8, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004207471	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 27, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	not provided	1	1	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Ataxia with Vitamin E Deficiency..

Schuelke M.

2005 May 20 [updated 2023 Mar 16]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(®) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.

PubMed [citation]

PMID:: 20301419

Normal spermatogenesis and sperm function in a subject affected by cerebellar ataxia due to congenital vitamin E deficiency.

Rossato M, Mariotti C.

Andrologia. 2014 Apr;46(3):322-4. doi: 10.1111/and.12076. Epub 2013 Feb 28.

PubMed [citation]

PMID:: 23445347

See all PubMed Citations (9)

Details of each submission

From GeneReviews, SCV000086769.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	not provided	not provided	not provided	Assert pathogenicity		not provided	not provided	not provided	not provided

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000967687.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (6)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		1	not provided	1	not provided

From Mendelics, SCV001137639.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Myriad Genetics, Inc., SCV001194120.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001363570.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Centre for Mendelian Genomics, University Medical Centre Ljubljana, SCV001367372.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV001461510.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV002022475.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004207471.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 24, 2024

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