ClinVar Miner

Submissions for variant NM_000370.3(TTPA):c.400C>T (p.Arg134Ter) (rs121917851)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000055797 SCV000220490 likely pathogenic Familial isolated deficiency of vitamin E 2014-07-08 criteria provided, single submitter literature only
Integrated Genetics/Laboratory Corporation of America RCV000055797 SCV000920331 pathogenic Familial isolated deficiency of vitamin E 2018-12-24 criteria provided, single submitter clinical testing Variant summary: TTPA c.400C>T (p.Arg134X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.6e-05 in 246084 control chromosomes (gnomAD). c.400C>T has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Ataxia with Vitamin E Deficiency (Cavalier 1998, Euch-Fayache 2014, Elkamil 2015). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000818142 SCV000958740 pathogenic not provided 2019-11-29 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg134*) in the TTPA gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs121917851, ExAC 0.02%). This variant has been reported as homozygous and/or in combination with other TTPA variants in several individuals affected with ataxia with isolated vitamin E deficiency (PMID: 9463307, 25614784, 22696689, 12470185). ClinVar contains an entry for this variant (Variation ID: 9141). Loss-of-function variants in TTPA are known to be pathogenic (PMID: 9463307, 25066259, 26068213). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000009712 SCV000029930 pathogenic Ataxia, Friedreich-like, with isolated vitamin E deficiency 1998-02-01 no assertion criteria provided literature only
GeneReviews RCV000055797 SCV000086766 pathologic Familial isolated deficiency of vitamin E 2013-06-27 no assertion criteria provided curation Converted during submission to Pathogenic.

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