rs387906733

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PP1_Moderate PP3 PS3_Moderate PS4_Supporting PM2_Supporting

This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CV30004/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: TRNH unassigned_transcript_4812 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: Likely_pathogenic. The variant received 7 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000387441.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-TH	ENST00000387441.1	TSL:6	n.64T>C		non_coding_transcript_exon	Exon 1 of 1
	MT-ND5	ENST00000361567.2	TSL:6	c.-136T>C		upstream_gene	N/A	ENSP00000354813.2
	MT-ND4	ENST00000361381.2	TSL:6	c.*64T>C		downstream_gene	N/A	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

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	-	MELAS syndrome (1)
1	-	-	Mitochondrial disease (1)
1	-	-	Mitochondrial non-syndromic sensorineural hearing loss (1)

Computational scores

Source: dbNSFP v4.9

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;