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

gnomAD frequency: 0.00002  dbSNP: rs35916840

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000522097	SCV000617806	pathogenic	not provided	2017-09-08	criteria provided, single submitter	clinical testing	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.
Counsyl	RCV000055804	SCV000800714	uncertain significance	Familial isolated deficiency of vitamin E	2018-05-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000055804	SCV002511487	pathogenic	Familial isolated deficiency of vitamin E	2022-04-07	criteria provided, single submitter	clinical testing	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000522097	SCV003440859	uncertain significance	not provided	2022-07-31	criteria provided, single submitter	clinical testing	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.
Baylor Genetics	RCV000055804	SCV004207493	likely pathogenic	Familial isolated deficiency of vitamin E	2024-02-15	criteria provided, single submitter	clinical testing
GeneReviews	RCV000055804	SCV000086773	not provided	Familial isolated deficiency of vitamin E		no assertion provided	literature only