chrM-5591-G-A

Variant names:

• chrM-5591-G-A
• rs121434458
• unassigned_transcript_4795:c.65C>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PP1_Moderate PS3_Supporting PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.5591G>A variant in MT-TA has been reported in one individual with primary mitochondrial disease (PMIDs: 16476954, 29139113). This was a male who presented in his 40s with progressive muscle weakness, myalgia, elevated creatine kinase (CK), and lactate. Muscle biopsy noted COX deficient fibers, increased subsarcolemmal mitochondrial accumulation, and electron transport chain complexes I, III, and IV deficiency. Heteroplasmy ranged from 79% (blood) to >99% (hair shaft). This variant segregated with disease manifestations in this family as an unaffected younger brother had the variant present at 67% heteroplasmy in urine and an unaffected older brother had undetectable levels of the variant in urine (PP1_moderate; PMID:16476954). There are no reported de novo occurrences of this variant to our knowledge. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic (68.6 percentile) and HmtVAR predicts it to be pathogenic score of 1 (PP3). Single fiber testing showed higher levels of the variant in COX-negative fibers (99.5%) than in COX-positive fibers (72.3%), p 0.0001 (PS3_supporting, PMID:16476954). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. We note that two experts on this panel felt likely pathogenic was a more appropriate classification given the functional evidence of impact however the majority agreed with uncertain significance. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on March 11, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PP1_moderate, PS3_supporting, PP3, PM2_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA254845/MONDO:0044970/015

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 0)
• Consequence: TRNA unassigned_transcript_4795 missense
• Scores: Mitotip Uncertain 15
• Clinical Significance: Uncertain significance reviewed by expert panel P:3 U:1 O:1 Myopathy
• Conservation: PhyloP100: 2.27
• Publications: 3 publications found

Genes affected

TRNA (HGNC:7475): (mitochondrially encoded tRNA alanine)

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]

TRNN (HGNC:7493): (mitochondrially encoded tRNA asparagine)

TRNW (HGNC:7501): (mitochondrially encoded tRNA tryptophan)

TRNC (HGNC:7477): (mitochondrially encoded tRNA cysteine)

TRNY (HGNC:7502): (mitochondrially encoded tRNA tyrosine)

TRNY Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PS3: 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: ENST00000387392.1. 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-TA	ENST00000387392.1	TSL:6	n.65C>T		non_coding_transcript_exon	Exon 1 of 1
	MT-ND2	ENST00000361453.3	TSL:6	c.*80G>A		downstream_gene	N/A	ENSP00000355046.4
	MT-TW	ENST00000387382.1	TSL:6	n.*12G>A		downstream_gene	N/A

Frequencies

Mitomap GenBank AF: 0.0 AC: 0

Gnomad homoplasmic AF: 0.0 AC: 0 AN: 56420

Gnomad heteroplasmic AF: 0.000018 AC: 1 AN: 56420

Mitomap

Disease(s): Myopathy

Status: Reported

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	1	-	Mitochondrial disease (2)
1	-	-	Inborn mitochondrial myopathy (1)
1	-	-	MELAS syndrome (1)
-	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	15
Hmtvar	Pathogenic	1.0
PhyloP100		2.3

Other links and lift over

dbSNP: rs121434458; hg19: chrM-5592; COSMIC: COSV106107932;