Submissions for variant NM_000370.3(TTPA):c.358G>A (p.Ala120Thr)

gnomAD frequency: 0.00008  dbSNP: rs143010236

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000055796	SCV000800616	uncertain significance	Familial isolated deficiency of vitamin E	2017-11-14	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000800124	SCV000939824	pathogenic	not provided	2024-01-14	criteria provided, single submitter	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.
Baylor Genetics	RCV000055796	SCV001163580	likely pathogenic	Familial isolated deficiency of vitamin E	2024-03-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000055796	SCV002571924	likely pathogenic	Familial isolated deficiency of vitamin E	2022-08-10	criteria provided, single submitter	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.
GeneReviews	RCV000055796	SCV000086765	not provided	Familial isolated deficiency of vitamin E		no assertion provided	literature only
Natera, Inc.	RCV000055796	SCV001461513	likely pathogenic	Familial isolated deficiency of vitamin E	2020-09-16	no assertion criteria provided	clinical testing