Submissions for variant NM_000360.4(TH):c.391T>G (p.Phe131Val)

gnomAD frequency: 0.00017  dbSNP: rs200536568

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001356362	SCV001786366	uncertain significance	not provided	2025-03-31	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV001273883	SCV002213050	uncertain significance	Autosomal recessive DOPA responsive dystonia	2022-08-23	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 162 of the TH protein (p.Phe162Val). This variant is present in population databases (rs200536568, gnomAD 0.03%). This missense change has been observed in individual(s) with Parkinson disease (PMID: 27185167). This variant is also known as c.391T>G p.(Phe131Val). ClinVar contains an entry for this variant (Variation ID: 643112). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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.
Fulgent Genetics, Fulgent Genetics	RCV001273883	SCV002791447	uncertain significance	Autosomal recessive DOPA responsive dystonia	2021-07-09	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001273883	SCV001457468	uncertain significance	Autosomal recessive DOPA responsive dystonia	2020-04-12	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356362	SCV001551508	uncertain significance	not provided		no assertion criteria provided	clinical testing	The TH p.Phe162Val variant was not identified in the literature but was identified in dbSNP (ID: rs200536568), LOVD 3.0 and ClinVar (classified as uncertain significance by Invitae). The variant was identified in control databases in 50 of 272994 chromosomes at a frequency of 0.0001832 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 45 of 123132 chromosomes (freq: 0.000366), Other in 1 of 6982 chromosomes (freq: 0.000143) and Latino in 4 of 35114 chromosomes (freq: 0.000114), but was not observed in the African, Ashkenazi Jewish, East Asian, European (Finnish), or South Asian populations. The p.Phe162 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001356362	SCV001744340	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001356362	SCV001973344	uncertain significance	not provided		no assertion criteria provided	clinical testing