ClinVar Miner

Submissions for variant NM_000370.3(TTPA):c.205-1G>C (rs886040963)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000411832 SCV000485719 likely pathogenic Familial isolated deficiency of vitamin E 2016-02-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000411832 SCV001363568 pathogenic Familial isolated deficiency of vitamin E 2019-11-04 criteria provided, single submitter clinical testing Variant summary: TTPA c.205-1G>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. Loss of function is considered to be the mechanism of disease in patients with Ataxia with Vitamin E Deficiency (AVED). The variant allele was found at a frequency of 8.1e-06 in 248416 control chromosomes. c.205-1G>C has been reported in the literature in compound heterozygosity in at-least one a well-phenotyped individual of Tunisian descent affected with AVED (example, Cavalier_1998) and has subsequently been cited in other reports (example, Hoshino_1999, Euch-Fayache_2014). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Based on the evidence outlined above and the well understood correlation of loss of function alleles in the pathophysiology of AVED, the variant was classified as pathogenic.
Invitae RCV001215990 SCV001387761 pathogenic not provided 2019-09-20 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 1 of the TTPA gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). Disruption of this splice site has been observed in individuals affected with ataxia with vitamin E deficiency (PMID: 9463307, 24369383). ClinVar contains an entry for this variant (Variation ID: 370407). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TTPA are known to be pathogenic (PMID: 9463307, 26068213). For these reasons, this variant has been classified as Pathogenic.

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