rs193303034

Variant names:

• chrM-4336-T-C
• rs41456348
• unassigned_transcript_4791:c.65A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The m.4336T>C variant in MT-TQ was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel on February 12, 2024. This variant has not been reported in the medical literature as causative in individuals or families with primary mitochondrial disease to our knowledge. However, this variant has been reported to be associated with Parkinson and Alzheimer diseases. There are many occurrences of this variant in healthy population databases, including in gnomAD v3.1.2 (737/56,424 or 1.306%), in the Helix dataset (3,949/195,983 or 2.015%), and in the GenBank dataset (535/61,134 or 0.875%), and this variant is seen across haplogroups including haplogroups H, U, A, B, J, HV, K, L3, M, Z, T, C, and V (BA1). Computational predictors are discordant as MitoTIP suggests this variant is benign (37.7 percentile) and HmtVAR predicts it to be pathogenic (0.4). In summary, as association studies linking this variant with Parkinson and Alzheimer diseases are outside the scope of this curation, this variant meets criteria to be classified as benign 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 February 12, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): BA1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA340926/MONDO:0044970/014

• Frequency: Mitomap GenBank: 𝑓 0.0088 (AC: 535)
• Consequence: TRNQ unassigned_transcript_4791 stop_lost
• Scores: Mitotip Uncertain 11
• Clinical Significance: Benign reviewed by expert panel P:1 U:1 B:4 ADPD-/-Hearing-Loss-&-Migraine-/-autism-spectrum-/-intellectual-disability
• Conservation: PhyloP100: -1.81
• Publications: 10 publications found

Genes affected

TRNQ (HGNC:7495): (mitochondrially encoded tRNA glutamine)

MT-ND2 (HGNC:7456): (mitochondrially encoded NADH dehydrogenase 2) 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; multiple sclerosis; myocardial infarction; neurodegenerative disease (multiple); and urinary bladder cancer. [provided by Alliance of Genome Resources, Apr 2022]

MT-ND1 (HGNC:7455): (mitochondrially encoded NADH dehydrogenase 1) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly. Located in mitochondrial membrane. Part of mitochondrial respiratory chain complex I. Implicated in several diseases, including MELAS syndrome; neurodegenerative disease (multiple); optic nerve disease (multiple); toxic shock syndrome; and type 2 diabetes mellitus. Biomarker of Alzheimer's disease; Parkinson's disease; and multiple sclerosis. [provided by Alliance of Genome Resources, Apr 2022]

TRNM (HGNC:7492): (mitochondrially encoded tRNA methionine)

TRNI (HGNC:7488): (mitochondrially encoded tRNA isoleucine)

TRNI Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• Leigh syndrome

  Inheritance: Mitochondrial Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRNQ	unassigned_transcript_4791	c.65A>G	p.Ter22Trpext*?	stop_lost	Exon 1 of 1
ND2	unassigned_transcript_4793	c.-134T>C		upstream_gene_variant
TRNM	unassigned_transcript_4792	c.-66T>C		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ND2	ENST00000361453.3	c.-134T>C		upstream_gene_variant		6		ENSP00000355046.4
MT-ND1	ENST00000361390.2	c.*74T>C		downstream_gene_variant		6		ENSP00000354687.2

Frequencies

Mitomap GenBank AF: 0.0088 AC: 535

Gnomad homoplasmic AF: 0.013 AC: 737 AN: 56424

Gnomad heteroplasmic AF: 0.000018 AC: 1 AN: 56424

Alfa AF: 0.0197 Hom.: 1904

Mitomap

Disease(s): ADPD-/-Hearing-Loss-&-Migraine-/-autism-spectrum-/-intellectual-disability

Status: Unclear

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Uncertain:1 Benign:4

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:2

Aug 17, 2020

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sensorineural deafness and migraine Pathogenic:1

Jun 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Uncertain:1

May 26, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mitochondrial disease Benign:1

Feb 12, 2024

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

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The m.4336T>C variant in MT-TQ was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel on February 12, 2024. This variant has not been reported in the medical literature as causative in individuals or families with primary mitochondrial disease to our knowledge. However, this variant has been reported to be associated with Parkinson and Alzheimer diseases. There are many occurrences of this variant in healthy population databases, including in gnomAD v3.1.2 (737/56,424 or 1.306%), in the Helix dataset (3,949/195,983 or 2.015%), and in the GenBank dataset (535/61,134 or 0.875%), and this variant is seen across haplogroups including haplogroups H, U, A, B, J, HV, K, L3, M, Z, T, C, and V (BA1). Computational predictors are discordant as MitoTIP suggests this variant is benign (37.7 percentile) and HmtVAR predicts it to be pathogenic (0.4). In summary, as association studies linking this variant with Parkinson and Alzheimer diseases are outside the scope of this curation, this variant meets criteria to be classified as benign 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 February 12, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): BA1. -

MELAS syndrome Benign:1

Jul 12, 2019

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NC_012920.1:m.4336T>C variant in MT-TQ gene is interpreted to be a Benign variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes reported in the guidelines: BS1, BS4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	11
Hmtvar	Pathogenic	0.40
PhyloP100		-1.8

Other links and lift over

dbSNP: rs41456348; hg19: chrM-4337;