Submissions for variant NM_000370.3(TTPA):c.552G>A (p.Thr184=)

gnomAD frequency: 0.00002  dbSNP: rs181109321

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000415204	SCV000493063	likely pathogenic	Familial isolated deficiency of vitamin E	2016-12-08	criteria provided, single submitter	research
Fulgent Genetics, Fulgent Genetics	RCV000415204	SCV000894449	likely pathogenic	Familial isolated deficiency of vitamin E	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001379026	SCV001576746	likely pathogenic	not provided	2023-12-14	criteria provided, single submitter	clinical testing	This sequence change affects codon 184 of the TTPA mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the TTPA protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs181109321, gnomAD 0.004%). This variant has been observed in individuals with TTPA-related conditions (PMID: 9270601, 9931538). ClinVar contains an entry for this variant (Variation ID: 374211). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in exon 3 skipping and introduces a premature termination codon (PMID: 9931538). The resulting mRNA is expected to undergo nonsense-mediated decay. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Centogene AG - the Rare Disease Company	RCV000415204	SCV002059865	likely pathogenic	Familial isolated deficiency of vitamin E	2019-11-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000415204	SCV002547992	pathogenic	Familial isolated deficiency of vitamin E	2022-05-17	criteria provided, single submitter	clinical testing	Variant summary: TTPA c.552G>A (p.Thr184Thr) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: One predicts the variant abolishes a 5' splicing donor site, two predict the variant weakens a 5' donor site, and two predict the variant creates a 3' acceptor site. At least two publications report experimental evidence that this variant affects mRNA splicing, producing a shortened mRNA transcript which lacks exon 3 (Tamaru_1997, Schuelke_1999). The mis-splicing is predicted to result in a shift in reading frame and a premature stop codon producing a truncated protein lacking the domains encoded by exons 3 to 5 (Schuelke_1999). The variant allele was found at a frequency of 2e-05 in 251242 control chromosomes. c.552G>A has been reported in the literature in individuals affected with Ataxia With Vitamin E Deficiency (Tamaru_1997, Schuelke_1999). These data indicate that the variant is likely to be associated with disease. Three clinical diagnostic laboratories and one research institution have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000415204	SCV004207482	likely pathogenic	Familial isolated deficiency of vitamin E	2024-02-25	criteria provided, single submitter	clinical testing
OMIM	RCV001810447	SCV000029931	pathogenic	Ataxia, Friedreich-like, with isolated vitamin E deficiency	1999-02-01	no assertion criteria provided	literature only
Genetic Services Laboratory, University of Chicago	RCV001379026	SCV003839190	likely pathogenic	not provided	2022-08-13	no assertion criteria provided	clinical testing	DNA sequence analysis of the TTPA gene demonstrated a sequence change, c.552G>A, in exon 3 that results in a synonymous amino acid change, p.Thr184Thr, in the apparent homozygous state. This sequence change occurs at the last base of exon 3 and in-silico splice prediction programs predict that this sequence change disrupts the canonical splice donor site at intron 3. RNA studies have demonstrated that this sequence change leads to the creation of an abnormal transcript lacking exon 3, and results in a premature stop codon (PMID: 9270601). This sequence change has been previously described in the homozygous state in individuals with ataxia with isolated vitamin E deficiency (PMID: 9270601, 9931538). This sequence change has been described in the gnomAD database in a total of 5 individuals, which corresponds to a frequency of 0.002% in the overall population (dbSNP rs181109321). Based on these collective evidences, this variant is considered likely pathogenic.