Submissions for variant NM_000370.3(TTPA):c.487del (p.Trp163fs)

dbSNP: rs397515378

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169325	SCV000220659	likely pathogenic	Familial isolated deficiency of vitamin E	2014-08-29	criteria provided, single submitter	literature only
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000169325	SCV000744349	pathogenic	Familial isolated deficiency of vitamin E	2015-09-21	criteria provided, single submitter	clinical testing
Invitae	RCV000794809	SCV000934241	pathogenic	not provided	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp163Glyfs*13) 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 (rs748164236, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with ataxia with vitamin E deficiency (PMID: 8602747, 9463307, 12907280, 15300460, 27274910). This variant is also known as 485delT, 486delT. ClinVar contains an entry for this variant (Variation ID: 188951). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169325	SCV001363569	pathogenic	Familial isolated deficiency of vitamin E	2019-02-19	criteria provided, single submitter	clinical testing	Variant summary: TTPA c.487delT (p.Trp163GlyfsX13) 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 2.9e-05 in 277072 control chromosomes (gnomAD). c.487delT has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Ataxia with Vitamin E Deficiency, which vitamin E levels were significantly decreased (<10%) (Hentati 1996, Cavalier 1998, Becker 2016). These data indicate that the variant is very likely to be associated with disease. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000169325	SCV002814184	pathogenic	Familial isolated deficiency of vitamin E	2022-03-24	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000169325	SCV004207480	pathogenic	Familial isolated deficiency of vitamin E	2023-08-18	criteria provided, single submitter	clinical testing
OMIM	RCV000009709	SCV000029927	pathogenic	Ataxia, Friedreich-like, with isolated vitamin E deficiency	1996-03-01	no assertion criteria provided	literature only
GeneReviews	RCV000169325	SCV000086768	not provided	Familial isolated deficiency of vitamin E		no assertion provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000169325	SCV000734616	pathogenic	Familial isolated deficiency of vitamin E		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000794809	SCV001956115	pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000169325	SCV002083342	pathogenic	Familial isolated deficiency of vitamin E	2021-02-26	no assertion criteria provided	clinical testing