rs575326605

Variant names:

• chr11-2165338-G-A
• rs575326605
• NM_000360.4:c.1228C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-2165338-G-A
• chr11-2165338-G-C
• chr11-2165338-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM5 PP5

The NM_000360.4(TH):​c.1228C>T​(p.Arg410Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000627 in 1,611,846 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R410L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000066 (0 hom.)
• Consequence: TH NM_000360.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:3
• Conservation: PhyloP100: 0.351

Genes affected

TH (HGNC:11782): (tyrosine hydroxylase) The protein encoded by this gene is involved in the conversion of tyrosine to dopamine. It is the rate-limiting enzyme in the synthesis of catecholamines, hence plays a key role in the physiology of adrenergic neurons. Mutations in this gene have been associated with autosomal recessive Segawa syndrome. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-2165337-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2919265.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP5: Variant 11-2165338-G-A is Pathogenic according to our data. Variant chr11-2165338-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 573670.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=4, Pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TH	NM_000360.4	c.1228C>T	p.Arg410Trp	missense_variant	Exon 12 of 13	ENST00000352909.8	NP_000351.2
TH	NM_199292.3	c.1321C>T	p.Arg441Trp	missense_variant	Exon 13 of 14		NP_954986.2
TH	NM_199293.3	c.1309C>T	p.Arg437Trp	missense_variant	Exon 13 of 14		NP_954987.2
TH	XM_011520335.3	c.1240C>T	p.Arg414Trp	missense_variant	Exon 12 of 13		XP_011518637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TH	ENST00000352909.8	c.1228C>T	p.Arg410Trp	missense_variant	Exon 12 of 13	1	NM_000360.4	ENSP00000325951.4

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152140 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000225 AC: 56 AN: 248838 AF XY: 0.000193

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000381

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000665 AC: 97 AN: 1459588 Hom.: 0 Cov.: 32 AF XY: 0.0000716 AC XY: 52 AN XY: 726116

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33480

Gnomad4 AMR exome AF: 0.00101 AC: 45 AN: 44724

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26136

Gnomad4 EAS exome AF: 0.000781 AC: 31 AN: 39698

Gnomad4 SAS exome AF: 0.000185 AC: 16 AN: 86254

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 51182

Gnomad4 NFE exome AF: 0.00000270 AC: 3 AN: 1111972

Gnomad4 Remaining exome AF: 0.0000331 AC: 2 AN: 60376

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152258 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74444

Gnomad4 AFR AF: 0.0000481 AC: 0.0000481371 AN: 0.0000481371

Gnomad4 AMR AF: 0.0000654 AC: 0.0000653509 AN: 0.0000653509

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000207 AC: 0.000207297 AN: 0.000207297

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.00 AC: 0 AN: 0

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.0000256 Hom.: 0

Bravo AF: 0.000106

ExAC AF: 0.000140 AC: 17

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive DOPA responsive dystonia Pathogenic:6 Uncertain:1

Mar 19, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 11, 2023

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 17, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 441 of the TH protein (p.Arg441Trp). This variant is present in population databases (rs575326605, gnomAD 0.1%). This missense change has been observed in individual(s) with clinical features of TH-related dystonia (PMID: 27619486, 37840187; internal data). 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 c.1228C>T . ClinVar contains an entry for this variant (Variation ID: 573670). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt TH protein function with a positive predictive value of 80%. This variant disrupts the p.Arg441 amino acid residue in TH. Other variant(s) that disrupt this residue have been observed in individuals with TH-related conditions (PMID: 23939262, 27619486), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

May 21, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TH c.1321C>T (p.Arg441Trp) aka c.1228C>T (p.Arg410Trp) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal (IPR019774) of the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant allele was found at a frequency of 0.00023 in 248838 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TH causing Segawa Syndrome, Autosomal Recessive (0.00023 vs 0.0011), allowing no conclusion about variant significance. c.1321C>T has been observed in individual(s) affected with Segawa Syndrome, Autosomal Recessive (Haugarvoll_2011, Yan_2017, Li_2021, Zhang_2023, internal_testing). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23939262, 27619486, 34054692, 37840187). ClinVar contains an entry for this variant (Variation ID: 573670). Based on the evidence outlined above, the variant was classified as pathogenic. -

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed missense c.1228C>T(p.Arg410Trp) / c.1321C>T (p.Arg441Trp) variant in TH gene has been reported previously in individual(s) affected with TH associated Segawa Syndrome (Yan YP, et al., 2017). The p.Arg410Trp variant has been reported with allele frequency of 0.02% in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic / Uncertain Significance (multiple submissions). Multiple lines of computational evidences (Polyphen - Probably damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid change at this position on TH gene is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 410 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties. Another missense variant [c.1322G>C (p.Arg441Pro] on the same residue of this gene has previously been reported to be disease causing (Haugarvoll K & Bindoff LA., 2011), suggesting that this residue might be of clinical significance. For these reasons, this variant has been classified as Likely Pathogenic. -

Mar 06, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 23, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:2

Oct 26, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27619486) -

Sep 30, 2024

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity. (http://gnomad.broadinstitute.org) This variant has been identified in at least one individual with clinical features associated with this gene. This variant segregates with disease in at least one family. Polyphen and MutationTaster predict this amino acid change may be damaging to the protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.098	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;.;.;.
Eigen	Benign	0.16
Eigen_PC	Benign	-0.061
FATHMM_MKL	Benign	0.62	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Uncertain	0.65	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	M;.;.;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-6.2	D;D;.;D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0010	D;D;.;D
Sift4G	Uncertain	0.014	D;D;D;D
Polyphen		1.0	D;D;.;D
Vest4		0.77
MutPred		0.52		Loss of disorder (P = 0.0143);.;.;.;
MVP		0.96
MPC		1.6
ClinPred		0.33	T
GERP RS		2.7
Varity_R		0.91
gMVP		0.86
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs575326605; hg19: chr11-2186568;