rs387906736

Variant names:

• chrM-5556-G-A
• rs387906736
• unassigned_transcript_4794:c.45G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 2 ACMG points: 2P and 0B. PS3_Supporting PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.5556G>A variant in MT-TW has been reported in one individual with mitochondrial disease to date (PMID:19809478). This was a girl with feeding difficulty and reflux onset shortly after birth and developmental regression beginning at age seven months. She also had constipation, failure to thrive, and died at 13 months due to respiratory insufficiency. She had metabolic acidosis and elevated blood and cerebrospinal fluid lactate. There was reduced activities of complexes I, III, and IV in skeletal muscle and fibroblasts, and reduced levels of fully assembled complexes I, III, IV, and V in fibroblast cell line. Mitochondrial protein synthesis and tRNA tryptophan levels were reduced in patient fibroblasts. The variant was present at 92% heteroplasmy in fibroblasts and 93% in skeletal muscle. The variant was not detectable in mother’s blood, hair, urine, or skeletal muscle (PM6_supporting; PMID:27450679). This variant is absent in the MITOMAP GenBank dataset, gnomAD v3.1.2, and the Helix dataset (PM2_supporting). In silico prediction tools are conflicting as the computational predictor MitoTIP suggests this variant is tolerated (44.5 percentile) but HmtVAR predicts it to be deleterious (score of 0.85). Cybrids with high heteroplasmy levels (90%, 93%, 96%) were generated and showed a pattern consistent with patient fibroblasts, and tRNA tryptophan levels were reduced in cybrids to 33% (PS3_supporting; PMID:19809478). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease however, after extensive discussion, this Expert Panel elected to modify the classification to likely pathogenic given the high heteroplasmy levels correlating with a severe phenotype with confirmed de novo status of the variant and compelling functional validation. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on May 28, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PM6_supporting, PM2_supporting, PS3_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA128833/MONDO:0044970/015

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 0)
• Consequence: TRNW unassigned_transcript_4794 synonymous
• Scores: Mitotip Uncertain 12
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 Combined-OXPHOS-defects,Mito-encephalomyopathy
• Conservation: PhyloP100: 4.97
• Publications: 1 publications found

Genes affected

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

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)

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

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

TRNC Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 2 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000387382.1. 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-TW	ENST00000387382.1	TSL:6	n.45G>A		non_coding_transcript_exon	Exon 1 of 1
	MT-ND2	ENST00000361453.3	TSL:6	c.*45G>A		downstream_gene	N/A	ENSP00000355046.4
	MT-TA	ENST00000387392.1	TSL:6	n.*31C>T		downstream_gene	N/A

Frequencies

Mitomap GenBank AF: 0.0 AC: 0

Mitomap

Disease(s): Combined-OXPHOS-defects,Mito-encephalomyopathy

Status: Reported,Reported

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	Mitochondrial disease (1)
1	-	-	Mitochondrial encephalomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	12
Hmtvar	Pathogenic	0.85
PhyloP100		5.0

Other links and lift over

dbSNP: rs387906736; hg19: chrM-5557;