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

gnomAD frequency: 0.00004  dbSNP: rs121917851

Total submissions: 10

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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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	2024-01-20	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. Loss-of-function variants in TTPA are known to be pathogenic (PMID: 9463307, 26068213). This variant is present in population databases (rs121917851, gnomAD 0.004%). This premature translational stop signal has been observed in individuals with ataxia with isolated vitamin E deficiency (PMID: 9463307, 12470185, 22696689, 25614784). ClinVar contains an entry for this variant (Variation ID: 9141). For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics Inc	RCV000818142	SCV001475830	pathogenic	not provided	2022-11-07	criteria provided, single submitter	clinical testing	This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene.
CeGaT Center for Human Genetics Tuebingen	RCV000818142	SCV001747566	pathogenic	not provided	2021-04-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000818142	SCV001786515	pathogenic	not provided	2023-04-20	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 12899840, 12470185, 25525159, 20301419, 9463307, 22696689, 24369383, 19566498, 25614784, 32979145, 31589614, 32928973)
Baylor Genetics	RCV000055797	SCV004207476	pathogenic	Familial isolated deficiency of vitamin E	2023-09-19	criteria provided, single submitter	clinical testing
OMIM	RCV000009712	SCV000029930	pathogenic	Ataxia, Friedreich-like, with isolated vitamin E deficiency	1998-02-01	no assertion criteria provided	literature only
GeneReviews	RCV000055797	SCV000086766	not provided	Familial isolated deficiency of vitamin E		no assertion provided	literature only
Natera, Inc.	RCV000055797	SCV001461511	pathogenic	Familial isolated deficiency of vitamin E	2020-09-16	no assertion criteria provided	clinical testing