rs387906733

Variant names:

• chrM-12201-T-C
• rs387906733
• unassigned_transcript_4812:c.64T>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The ENST00000000000(TRNH):​c.64T>C​(p.Phe22Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Mitomap GenBank: Absent
• Consequence: TRNH ENST00000000000 missense
• 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
• Publications: 1 publications found

Genes affected

TRNH (HGNC:7487): (mitochondrially encoded tRNA histidine)

MT-ND5 (HGNC:7461): (mitochondrially encoded NADH dehydrogenase 5) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly. Part of mitochondrial respiratory chain complex I. Implicated in Leber hereditary optic neuropathy; Leigh disease; and MELAS syndrome. [provided by Alliance of Genome Resources, Apr 2022]

MT-ND4 (HGNC:7459): (mitochondrially encoded NADH dehydrogenase 4) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly. Part of mitochondrial respiratory chain complex I. Implicated in Leber hereditary optic neuropathy; Parkinson's disease; macular degeneration; and schizophrenia. Biomarker of Alzheimer's disease. [provided by Alliance of Genome Resources, Apr 2022]

TRNL2 (HGNC:7491): (mitochondrially encoded tRNA leucine 2 (CUN))

TRNS2 (HGNC:7498): (mitochondrially encoded tRNA serine 2 (AGU/C))

TRNS2 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: No frequency data in Mitomap. Probably very rare.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRNH	unassigned_transcript_4812	c.64T>C	p.Phe22Leu	missense_variant	Exon 1 of 1
ND5	unassigned_transcript_4815	c.-136T>C		upstream_gene_variant
TRNL2	unassigned_transcript_4814	c.-65T>C		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ND5	ENST00000361567.2	c.-136T>C		upstream_gene_variant		6		ENSP00000354813.2
MT-ND4	ENST00000361381.2	c.*64T>C		downstream_gene_variant		6		ENSP00000354961.2

Frequencies

Mitomap GenBank The variant is not present, suggesting it is rare .

Alfa AF: 0.00 Hom.: 0

Mitomap

Disease(s): Maternally-inherited-non-syndromic-deafness

Status: Cfrm-[LP]

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial disease Pathogenic:1

Apr 17, 2023

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

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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

Oct 01, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

MELAS syndrome Uncertain:1

Jul 12, 2019

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		-0.47

Other links and lift over

dbSNP: rs387906733; hg19: chrM-12202;