Submissions for variant NM_000370.3(TTPA):c.513_514insTT (p.Thr172fs)

gnomAD frequency: 0.00010  dbSNP: rs397515379

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000055800	SCV000967687	pathogenic	Familial isolated deficiency of vitamin E	2018-12-17	criteria provided, single submitter	clinical testing	The p.Thr172LeufsX5 variant in TTPA has been reported in at least 3 homozygous a nd 3 compound heterozygous individuals with ataxia and vitamin E deficiency (Oua hchi 1995, Hentati 1996, Cavalier 1998, Rossato 2014, Elkamil 2015). It has also been identified in 0.03% (38/129082) of European chromosomes by gnomAD (http:// gnomad.broadinstitute.org). However, this frequency is low enough to be consiste nt with a recessive carrier frequency. This variant has also been reported in Cl inVar (Variation ID #9139). This variant is predicted to cause a frameshift, whi ch alters the protein?s amino acid sequence beginning at position 172 and leads to a premature termination codon 5 amino acids downstream. This alteration is th en predicted to lead to a truncated or absent protein. Biallelic loss of functio n of the TTPA gene is an established disease mechanism in autosomal recessive at axia with vitamin E deficiency. In summary, this variant meets criteria to be cl assified as pathogenic for autosomal recessive ataxia with vitamin E deficiency. ACMG/AMP Criteria applied: PVS1, PM3_Strong, PM2_Supporting.
Mendelics	RCV000055800	SCV001137639	pathogenic	Familial isolated deficiency of vitamin E	2019-05-28	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000993523	SCV001146563	pathogenic	not provided	2019-03-20	criteria provided, single submitter	clinical testing	The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity.
GeneDx	RCV000993523	SCV001168316	pathogenic	not provided	2022-05-02	criteria provided, single submitter	clinical testing	Frameshift 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; This variant is associated with the following publications: (PMID: 7719340, 9463307, 8602747, 23445347, 31980526, 31589614, 32928973, 25614784)
Myriad Genetics, Inc.	RCV000055800	SCV001194120	pathogenic	Familial isolated deficiency of vitamin E	2020-01-03	criteria provided, single submitter	clinical testing	NM_000370.3(TTPA):c.513_514insTT(T172Lfs*5) is classified as pathogenic in the context of ataxia with vitamin E deficiency. Sources cited for classification include the following: PMID 9463307 and 15300460. Classification of NM_000370.3(TTPA):c.513_514insTT(T172Lfs*5) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
Invitae	RCV000993523	SCV001228826	pathogenic	not provided	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr172Leufs*5) 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 (rs397515379, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with ataxia with isolated vitamin E deficiency (PMID: 9463307, 9588854, 11013295, 12112220, 12470185, 15300460, 23445347). ClinVar contains an entry for this variant (Variation ID: 9139). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000055800	SCV001363570	pathogenic	Familial isolated deficiency of vitamin E	2019-11-22	criteria provided, single submitter	clinical testing	Variant summary: TTPA c.513_514insTT (p.Thr172LeufsX5) 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 0.00015 in 251276 control chromosomes (gnomAD). This frequency is not higher than the expected maximum for a pathogenic variant in TTPA causing Ataxia with Vitamin E Deficiency (0.00015 vs 0.002). c.513_514insTT has been reported in the literature in multiple homozygous- and compound heterozygote individuals affected with 'Ataxia with Vitamin E Deficiency' (e.g. Mariotti_2004). These data indicate that the variant is very likely to be associated with disease. A ClinVar submission (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000055800	SCV001367372	pathogenic	Familial isolated deficiency of vitamin E	2020-02-27	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS4_MOD,PM2.
CeGaT Center for Human Genetics Tuebingen	RCV000993523	SCV001502647	pathogenic	not provided	2020-07-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000055800	SCV002022475	pathogenic	Familial isolated deficiency of vitamin E	2021-09-08	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000055800	SCV004207471	pathogenic	Familial isolated deficiency of vitamin E	2023-10-15	criteria provided, single submitter	clinical testing
OMIM	RCV000009710	SCV000029928	pathogenic	Ataxia, Friedreich-like, with isolated vitamin E deficiency	1996-03-01	no assertion criteria provided	literature only
GeneReviews	RCV000055800	SCV000086769	not provided	Familial isolated deficiency of vitamin E		no assertion provided	literature only
Natera, Inc.	RCV000055800	SCV001461510	pathogenic	Familial isolated deficiency of vitamin E	2020-09-16	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000993523	SCV001551938	pathogenic	not provided		no assertion criteria provided	clinical testing	The TTPA p.T172Lfs*5 variant was identified in >15 patients with ataxia with vitamin E deficiency as a homozygous or compound heterozygous variant (Mariotti_2004_PMID:15300460; Elkamil_2005_PMID:25614784; Angelini_2002_PMID:12112220; Schuekle_2000_PMID:11013295; Cavalier_1998_PMID:9463307; Rossato_2014_PMID:23445347; Martinello_1998_PMID:9588854; Hentati_1996_PMID:8602747). The variant was identified in dbSNP (ID: rs397515379) and ClinVar (classified as pathogenic by Athena Diagnostics, Laboratory for Molecular Medicine, Counsyl and Mendelics). The variant was identified in control databases in 41 of 282676 chromosomes at a frequency of 0.000145 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 38 of 129082 chromosomes (freq: 0.000294), Other in 1 of 7218 chromosomes (freq: 0.000139), South Asian in 1 of 30600 chromosomes (freq: 0.000033) and Latino in 1 of 35388 chromosomes (freq: 0.000028), but was not observed in the African, Ashkenazi Jewish, East Asian, or European (Finnish) populations. The c.513_514insTT variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 172 and leads to a premature stop codon 5 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the TTPA gene are an established mechanism of disease in ataxia with vitamin E deficiency and are the type of variants expected to cause the disorder when foudn in the homozygous or compound heterozygous state. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.