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

dbSNP: rs397515377

Total submissions: 10

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 Genetics, 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	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu249Asnfs*15) in the TTPA gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 30 amino acid(s) of the TTPA protein. This variant is present in population databases (rs397515377, gnomAD 0.01%). This premature translational stop signal has been observed in individuals 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, and the functional significance of this variant is currently unknown. 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.
Fulgent Genetics, Fulgent Genetics	RCV000055806	SCV002801044	pathogenic	Familial isolated deficiency of vitamin E	2021-12-13	criteria provided, single submitter	clinical testing
3billion	RCV000055806	SCV003841700	pathogenic	Familial isolated deficiency of vitamin E	2023-02-23	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.006%). This variant was predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10%. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000009136 / PMID: 7719340 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Baylor Genetics	RCV000055806	SCV004207477	pathogenic	Familial isolated deficiency of vitamin E	2023-09-09	criteria provided, single submitter	clinical testing
OMIM	RCV000009707	SCV000029925	pathogenic	Ataxia, Friedreich-like, with isolated vitamin E deficiency	1995-02-01	no assertion criteria provided	literature only
GeneReviews	RCV000055806	SCV000086775	not provided	Familial isolated deficiency of vitamin E		no assertion provided	literature only
Natera, Inc.	RCV000055806	SCV001461508	pathogenic	Familial isolated deficiency of vitamin E	2020-09-16	no assertion criteria provided	clinical testing