ClinVar Miner

Submissions for variant NM_000370.3(TTPA):c.513_514insTT (p.Thr172fs) (rs397515379)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare 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 2019-02-27 criteria provided, single submitter clinical testing The c.513_514insTT variant in the TTPA gene has been reported previously in association with ataxia with isolated vitamin E deficiency when present in the homozygous state or when in trans with another TTPA variant (Hentati et al., 1996; Cavalier et al., 1998). The c.513_514insTT variant causes a frameshift starting with codon Threonine 172, changes this amino acid to a Leucine residue, and creates a premature Stop codon at position 5 of the new reading frame, denoted p.Thr172LeufsX5. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.513_514insTT variant is observed in 38/126614 (0.03%) alleles from individuals of non-Finnish European background, in large population cohorts and no individuals were reported to be homozygous (Lek et al., 2016). We interpret c.513_514insTT as a pathogenic variant.
Myriad Women's Health, 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 2020-10-06 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. This variant is present in population databases (rs397515379, ExAC 0.03%). This variant has been observed in several individuals affected with ataxia with isolated vitamin E deficiency (PMID: 9463307, 23445347, 11013295, 9588854, 15300460, 12112220, 12470185). ClinVar contains an entry for this variant (Variation ID: 9139). Loss-of-function variants in TTPA are known to be pathogenic (PMID: 9463307, 26068213). 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 Praxis fuer Humangenetik Tuebingen RCV000993523 SCV001502647 pathogenic not provided 2020-07-01 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 pathologic Familial isolated deficiency of vitamin E 2013-06-27 no assertion criteria provided curation Converted during submission to Pathogenic.
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.

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