ClinVar Miner

Submissions for variant NM_000360.4(TH):c.1300T>C (p.Ser434Pro)

gnomAD frequency: 0.00001  dbSNP: rs1367289835
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
3billion, Medical Genetics RCV001775267 SCV002012003 likely pathogenic Autosomal recessive DOPA responsive dystonia 2021-10-02 criteria provided, single submitter clinical testing It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000004, PM2). The variant was observed in trans with a pathogenic variant (NM_199292.2:c.698G>A) as compound heterozygous (3billion dataset, PM3). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.846, 3Cnet: 0.957, PP3). Patient is considered compatible with Segawa syndrome, recessive (PP4_P). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Labcorp Genetics (formerly Invitae), Labcorp RCV001775267 SCV002112214 likely pathogenic Autosomal recessive DOPA responsive dystonia 2023-12-21 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 465 of the TH protein (p.Ser465Pro). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with dopa-responsive dystonia (PMID: 33233562). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1320094). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TH protein function. 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.

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