ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs886040963
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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 2024-01-12 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. Variants that disrupt the donor or acceptor splice site 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). This variant is present in population databases (no rsID available, gnomAD 0.003%). Disruption of this splice site has been observed in individuals with ataxia with vitamin E deficiency (PMID: 9463307, 24369383). ClinVar contains an entry for this variant (Variation ID: 370407). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc. RCV000411832 SCV002060201 pathogenic Familial isolated deficiency of vitamin E 2021-11-03 criteria provided, single submitter clinical testing NM_000370.3(TTPA):c.205-1G>C is a canonical splice variant classified as pathogenic in the context of ataxia with vitamin E deficiency. c.205-1G>C has been observed in cases with relevant disease (PMID: 9463307, Esmer_2013_(no PMID; article)). Functional assessments of this variant are not available in the literature. c.205-1G>C has been observed in population frequency databases (gnomAD: AMR 0.003%). In summary, NM_000370.3(TTPA):c.205-1G>C is a canonical splice variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Baylor Genetics RCV000411832 SCV004207474 pathogenic Familial isolated deficiency of vitamin E 2023-10-10 criteria provided, single submitter clinical testing
Natera, Inc. RCV000411832 SCV002083346 pathogenic Familial isolated deficiency of vitamin E 2021-02-23 no assertion criteria provided clinical testing

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