NM_000360.4:c.23C>T
Variant summary
Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4
The NM_000360.4(TH):c.23C>T(p.Thr8Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000695 in 1,612,472 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T8T) has been classified as Likely benign.
Frequency
Consequence
NM_000360.4 missense
Scores
Clinical Significance
Conservation
Publications
- TH-deficient dopa-responsive dystoniaInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
- tyrosine hydroxylase deficiencyInheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, Myriad Women’s Health
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ACMG classification
Our verdict: Likely_benign. The variant received -1 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000657 AC: 10AN: 152168Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.0000808 AC: 20AN: 247550 AF XY: 0.0000894 show subpopulations
GnomAD4 exome AF: 0.0000698 AC: 102AN: 1460304Hom.: 0 Cov.: 31 AF XY: 0.0000840 AC XY: 61AN XY: 726530 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000657 AC: 10AN: 152168Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74336 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Autosomal recessive DOPA responsive dystonia Uncertain:2
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 8 of the TH protein (p.Thr8Met). This variant is present in population databases (rs373964946, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with TH-related conditions. ClinVar contains an entry for this variant (Variation ID: 576292). 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 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. -
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Inborn genetic diseases Uncertain:1
The c.23C>T (p.T8M) alteration is located in exon 1 (coding exon 1) of the TH gene. This alteration results from a C to T substitution at nucleotide position 23, causing the threonine (T) at amino acid position 8 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
not provided Uncertain:1
TH: PM2 -
Intellectual disability Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at