ClinVar Miner

Submissions for variant NM_000360.4(TH):c.646G>A (p.Gly216Ser)

gnomAD frequency: 0.00001  dbSNP: rs762304556
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001220234 SCV001392214 pathogenic Autosomal recessive DOPA responsive dystonia 2024-01-29 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 247 of the TH protein (p.Gly247Ser). This variant is present in population databases (rs762304556, gnomAD 0.02%). This missense change has been observed in individual(s) with dopa-responsive dystonia (PMID: 18554280, 20056467, 28087438, 29405179). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as Gly216Ser. ClinVar contains an entry for this variant (Variation ID: 948892). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects TH function (PMID: 24753243). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
NxGen MDx RCV001353113 SCV001548249 likely pathogenic Dystonia 5 2021-03-30 criteria provided, single submitter clinical testing This missense variant (c.739G>A) causes a protein change (p.Gly247Ser) at the second codon of exon 7 in the TH gene. Fossbakk et al. PMID: 24753243 indicated pathogenicity through functional studies showing that the substrate specificity and residual activity is diminished with significantly lower stability (PS3). Additional cases have been reported in PMID: 29405179 and 28087438. Some literature refers to this variant as G216S. In silico models for this variant have indicated numerous disease causing or damaging interpretations (PP3). We interpret c.739G>A to be likely pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001220234 SCV001821315 pathogenic Autosomal recessive DOPA responsive dystonia 2021-08-19 criteria provided, single submitter clinical testing Variant summary: TH c.739G>A (p.Gly247Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.6e-05 in 165638 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in TH causing Segawa Syndrome, Autosomal Recessive (6.6e-05 vs 0.0011), allowing no conclusion about variant significance. c.739G>A has been reported in the literature in multiple individuals affected with Segawa Syndrome (otherwise known as autosomal recessive dopa-responsive dystonia; Wu_2008, Mak_2010, Zhang_2017, Yang_2018, Chen_2020). Experimental evidence has shown the variant to result in reduced substrate specificity, residual activity and significantly lower stability (Fossabkk_2014). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity RCV001220234 SCV002016887 likely pathogenic Autosomal recessive DOPA responsive dystonia 2021-08-07 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV001220234 SCV002775519 likely pathogenic Autosomal recessive DOPA responsive dystonia 2021-11-28 criteria provided, single submitter clinical testing
GeneDx RCV003317458 SCV004021713 pathogenic not provided 2023-07-17 criteria provided, single submitter clinical testing Reported previously in the compound heterozygous state in patients with dystonia (Li et al., 2021); Reported previously in a patient with lower limb dystonia and a patient with limb twitching, hypotonia, and global delay; both patients harbored a second variant (phase unknown) (Mak et al., 2010); Published functional studies show that this variant causes impaired thermal stability, decreased tyrosine hydroxylase activity, and shifts substrate specificity from Tyrosine to Phenylalanine and Dopa (Fossbakk et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 27619486, 18554280, 32005694, 29405179, 32872068, 24753243, 34054692, 20056467)
Baylor Genetics RCV001220234 SCV004203833 pathogenic Autosomal recessive DOPA responsive dystonia 2024-02-28 criteria provided, single submitter clinical testing
Natera, Inc. RCV001220234 SCV002085332 pathogenic Autosomal recessive DOPA responsive dystonia 2020-08-12 no assertion criteria provided clinical testing

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