rs387906733

chrM-12201-T-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The ENST00000387441.1(MT-TH):n.64T>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★★★).

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-TH ENST00000387441.1 non_coding_transcript_exon
• Scores: Mitotip Uncertain 15
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 U:1 Maternally-inherited-non-syndromic-deafness
• Conservation: PhyloP100: -0.465

Genes affected

MT-TH (HGNC:7487): (mitochondrially encoded tRNA histidine)

TRNH (HGNC:):

MT-TS2 (HGNC:7498): (mitochondrially encoded tRNA serine 2 (AGU/C))

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: No frequency data in Mitomap. Probably very rare.
• PP3: Mitotip and hmtvar scores support pathogenic criterium.
• PP5: Variant M-12201-T-C is Pathogenic according to our data. Variant chrM-12201-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 30004.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRNH	TRNH.1	n.64T>C		non_coding_transcript_exon_variant	1/1
TRNS2	TRNS2.1			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MT-TH	ENST00000387441.1	n.64T>C		non_coding_transcript_exon_variant	1/1
MT-TS2	ENST00000387449.1			upstream_gene_variant

Frequencies

GnomAD4 exome Cov.: 0

We have no GnomAD4 genomes data on this position. Probably position not covered by the project.

Mitomap

Maternally-inherited-non-syndromic-deafness

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial disease Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen

Apr 17, 2023

The m.12201T>C variant in MT-TH has been reported in three families with features of primary mitochondrial disease (PS4_supporting). The first family reported was 5-generation Han Chinese family with late-onset non-syndromic deafness (PMIDs: 21931169, 24920829, 31819004, 32169613). A second case was reported in a Vietnamese cohort of children with non-syndromic hearing loss (https://www.ojhas.org/issue65/2018-1-6.html). The third case was reported in a cohort of individuals with dilated cardiomyopathy (PMID: 34991096). Seventeen of 35 matrilineal relatives in the first reported family exhibited variable severity and age at onset of sensorineural hearing loss and blood heteroplasmy levels correlated with both onset age and symptom severity (PP1_moderate). There are no reported de novo occurrences of this variant to our knowledge. Although there are several occurrences in population databases, the frequency is still low (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic (67th percentile) and HmtVAR predicts it to be pathogenic score of 0.5 (PP3). Cybrid studies show different classes of function defects including a decrease in the steady-state level of tRNAHis, diminished respiratory capacity, marked decreases in mtATP levels and membrane potential, increased reactive oxygen species (ROS) production, decreased melting temperature, conformational changes, and instability of the mutated tRNA, and HARS2 overexpression corrected the mitochondrial dysfunction (PS3_moderate; PMIDs: 24920829, 31819004). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on April 17, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PP1_moderate, PM2_supporting, PP3, PS3_moderate. -

Mitochondrial non-syndromic sensorineural hearing loss Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2011

- -

Juvenile myopathy, encephalopathy, lactic acidosis AND stroke Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

Jul 12, 2019

The NC_012920.1:m.12201T>C variant in MT-TH gene is interpreted to be a Unknown Significance variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes reported in the guidelines: PP3, BP6 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	15
Hmtvar	Pathogenic	0.50

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs387906733; hg19: chrM-12202;