NM_000370.3(TTPA):c.661C>T (p.Arg221Trp) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 27, 2026
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:: RCV000522097.6

Allele description [Variation Report for NM_000370.3(TTPA):c.661C>T (p.Arg221Trp)]

NM_000370.3(TTPA):c.661C>T (p.Arg221Trp)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

8q12.3

Genomic location:

Preferred name:

NM_000370.3(TTPA):c.661C>T (p.Arg221Trp)

HGVS:

NC_000008.11:g.63064208G>A
NG_016123.1:g.26846C>T
NM_000370.3:c.661C>TMANE SELECT
NP_000361.1:p.Arg221Trp
NC_000008.10:g.63976767G>A
NM_000370.2:c.661C>T
P49638:p.Arg221Trp

Protein change:

R221W

Links:

UniProtKB: P49638#VAR_022391; dbSNP: rs35916840

Molecular consequence:

NM_000370.3:c.661C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000617806	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Pathogenic (Sep 8, 2017)	germline	clinical testing	Citation Link,
SCV003440859	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 27, 2026)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 9463307, 31429931, 15065857, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000617806

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Pathogenic
(Sep 8, 2017)

germline

clinical testing

Citation Link,

SCV003440859

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 27, 2026)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	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

Citations

PubMed

Ataxia with isolated vitamin E deficiency: heterogeneity of mutations and phenotypic variability in a large number of families.

Cavalier L, Ouahchi K, Kayden HJ, Di Donato S, Reutenauer L, Mandel JL, Koenig M.

Am J Hum Genet. 1998 Feb;62(2):301-10.

PubMed [citation]

PMID:: 9463307
PMCID:: PMC1376876

Whole exome and targeted gene sequencing to detect pathogenic recessive variants in early onset cerebellar ataxia.

Shakya S, Kumari R, Suroliya V, Tyagi N, Joshi A, Garg A, Singh I, Kalikavil Puthanveedu D, Cherian A, Mukerji M, Srivastava AK, Faruq M.

Clin Genet. 2019 Dec;96(6):566-574. doi: 10.1111/cge.13625. Epub 2019 Sep 1.

PubMed [citation]

PMID:: 31429931

See all PubMed Citations (4)

Details of each submission

From GeneDx, SCV000617806.2

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

Description

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.

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003440859.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

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 individuals with ataxia with isolated vitamin E deficiency (PMID: 9463307, 31429931). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 65597). 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 disruptive. Experimental studies have shown that this missense change affects TTPA function (PMID: 15065857). For these reasons, this variant has been 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

Last Updated: Jul 14, 2026

ClinVar

Relating variation to medicine