ClinVar Miner

Submissions for variant NM_000370.3(TTPA):c.744del (p.Glu249fs) (rs397515377)

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Total submissions: 7
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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 RCV000055806 SCV000696612 pathogenic Familial isolated deficiency of vitamin E 2017-04-24 criteria provided, single submitter clinical testing Variant summary: The TTPA c.744delA (p.Glu249Asnfs) variant results in a premature termination codon, predicted to cause a truncated or absent TTPA protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in the large control database ExAC at a frequency of 0.000099 (12/121224 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic TTPA variant (0.0020412). The variant has been reported in over 100 patients of Tunisian and Algerian descent who were homozygous for the variant (Euch-Fayache_2014; Hamza_2015). Addtionally, the variant segregated with disease in several consanguineous families, providing strong evidence of pathogenicity. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000055806 SCV000965799 pathogenic Familial isolated deficiency of vitamin E 2015-01-01 criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000055806 SCV001194210 pathogenic Familial isolated deficiency of vitamin E 2019-12-09 criteria provided, single submitter clinical testing NM_000370.3(TTPA):c.744delA(aka E249Nfs*15) is classified as pathogenic in the context of ataxia with vitamin E deficiency. Sources cited for classification include the following: PMID 7719340, 12039660, 9463307 and 15953402. Classification of NM_000370.3(TTPA):c.744delA(aka E249Nfs*15) is based on the following criteria: The variant causes a premature termination codon that is not expected to be targeted by nonsense-mediated mRNA decay; however, literature evidence strongly supports pathogenicity. Please note: this variant was assessed in the context of healthy population screening.
Invitae RCV001046510 SCV001210415 pathogenic not provided 2020-09-14 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the TTPA gene (p.Glu249Asnfs*15). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 30 amino acids of the TTPA protein. This variant is present in population databases (rs397515377, ExAC 0.03%). This variant has been observed in individuals affected with ataxia with isolated vitamin E deficiency (PMID: 26068213). ClinVar contains an entry for this variant (Variation ID: 9136). Experimental studies and prediction algorithms are not available or were not evaluated for this variant, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000009707 SCV000029925 pathogenic Ataxia, Friedreich-like, with isolated vitamin E deficiency 1995-02-01 no assertion criteria provided literature only
GeneReviews RCV000055806 SCV000086775 pathologic Familial isolated deficiency of vitamin E 2013-06-27 no assertion criteria provided curation Converted during submission to Pathogenic.
Natera, Inc. RCV000055806 SCV001461508 pathogenic Familial isolated deficiency of vitamin E 2020-09-16 no assertion criteria provided clinical testing

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