chr11-2167905-C-G

Variant names:

• chr11-2167905-C-G
• rs80338892
• NM_000360.4:c.605G>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_000360.4(TH):​c.605G>C​(p.Arg202Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000686 in 1,458,642 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R202C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: TH NM_000360.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.96
• Publications: 33 publications found

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]

TH Gene-Disease associations (from GenCC):

• TH-deficient dopa-responsive dystonia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, G2P
• tyrosine hydroxylase deficiency

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health, ClinGen

ENSG00000295384 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 8 uncertain in NM_000360.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-2167906-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 640660.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000360.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TH	NM_000360.4	MANE Select	c.605G>C	p.Arg202Pro	missense	Exon 5 of 13	NP_000351.2	P07101-3
	TH	NM_199292.3		c.698G>C	p.Arg233Pro	missense	Exon 6 of 14	NP_954986.2	P07101-1
	TH	NM_199293.3		c.686G>C	p.Arg229Pro	missense	Exon 6 of 14	NP_954987.2	P07101-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TH	ENST00000352909.8	TSL:1 MANE Select	c.605G>C	p.Arg202Pro	missense	Exon 5 of 13	ENSP00000325951.4	P07101-3
	TH	ENST00000381178.5	TSL:1	c.698G>C	p.Arg233Pro	missense	Exon 6 of 14	ENSP00000370571.1	P07101-1
	TH	ENST00000381175.5	TSL:1	c.686G>C	p.Arg229Pro	missense	Exon 6 of 14	ENSP00000370567.1	P07101-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000686 AC: 10 AN: 1458642 Hom.: 0 Cov.: 33 AF XY: 0.00000689 AC XY: 5 AN XY: 725420

African (AFR) AF: 0.00 AC: 0 AN: 33440

American (AMR) AF: 0.00 AC: 0 AN: 44534

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26070

East Asian (EAS) AF: 0.00 AC: 0 AN: 39598

South Asian (SAS) AF: 0.00 AC: 0 AN: 85834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52018

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000720 AC: 8 AN: 1111124

Other (OTH) AF: 0.0000332 AC: 2 AN: 60262

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		3.0
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.97		Loss of MoRF binding (P = 0.0283)
MVP		0.99
MPC		0.37
ClinPred		0.99	D
GERP RS		3.1
PromoterAI		0.0083	Neutral
Varity_R		0.98
gMVP		0.96
Mutation Taster		=1/99	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs80338892; hg19: chr11-2189135;