Submissions for variant NM_000360.4(TH):c.1032C>G (p.Phe344Leu)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002593546	SCV002947839	uncertain significance	Autosomal recessive DOPA responsive dystonia	2022-08-09	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 375 of the TH protein (p.Phe375Leu). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with TH-related conditions (PMID: 19224593). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). Experimental studies have shown that this missense change affects TH function (PMID: 24753243). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002593546	SCV003928743	likely pathogenic	Autosomal recessive DOPA responsive dystonia	2023-04-04	criteria provided, single submitter	clinical testing	Variant summary: TH c.1125C>G (p.Phe375Leu) results in a non-conservative amino acid change located in the catalytic domain (Clot_2009) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.7e-06 in 210876 control chromosomes (gnomAD). c.1125C>G has been reported in the literature in the compound heterozygous state in an individual affected with dopa-responsive dystonia (autosomal recessive Segawa Syndrome) (Doummar_2009, Clot_2009). This report does not provide unequivocal conclusions about association of the variant with Segawa Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function and found that the variant results in approximately 10% of WT activity (Fossbakk_2014). One clinical diagnostic laboratory has submitted a clinical-significance assessment for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.