rs199474662

Variant names:

• chrM-3251-A-G
• rs199474662
• unassigned_transcript_4788:c.22A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 5 ACMG points: 5P and 0B. PS4_Moderate PS3_Supporting PP1 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.3251A>G variant in MT-TL1 has been reported in four unrelated individuals with primary mitochondrial disease to date. Age of onset ranged from the first decade of life to adulthood and clinical features in affected individuals were variably consistent with chronic progressive external ophthalmoplegia (CPEO), myoclonic epilepsy with ragged red fibers (MERRF), mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), and early death. Heteroplasmy ranged from 13-95% in affected individuals (PS4_moderate; PMIDs: 8265770, 38465286, 8786060, 30837005). This variant segregated with clinical manifestations in one family with CPEO, progressive muscle weakness, and early death. The variant was present in the proband at 81% in muscle and 13% in blood and was present in maternal cousins at heteroplasmy levels of 25-16% (PP1; PMID:8265770). 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). Computational predictors are conflicting (MitoTIP: 43.5%; HmtVAR: 0.75). Single fiber testing showed higher levels of the variant in COX-negative fibers (61%, range 15-88%) than in COX-positive fibers (28%, range 3%-86%; p<0.001; PS3_supporting, PMID:8786060). There is additional evidence showing deleterious effects of this variant on the tRNA (PMID:33380464). 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 compelling functional validation and consistent phenotype observed in reported cases. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on April 22, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PS4_moderate, PP1, PM2_supporting, PS3_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120565/MONDO:0044970/014

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 0)
• Consequence: TRNL1 unassigned_transcript_4788 missense
• Scores: Mitotip Uncertain 12
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4 MM-/-MELAS-with-chorea-ballism
• Conservation: PhyloP100: 0.908
• Publications: 2 publications found

Genes affected

TRNL1 (HGNC:7490): (mitochondrially encoded tRNA leucine 1 (UUA/G)) Implicated in cardiomyopathy. [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]

MT-RNR2 (HGNC:7471): (mitochondrially encoded 16S RNA) Enables G protein-coupled receptor binding activity; protein self-association; and receptor antagonist activity. Involved in several processes, including leukocyte chemotaxis; negative regulation of cell death; and negative regulation of neuroinflammatory response. Located in several cellular components, including mitochondrion; perinuclear region of cytoplasm; and sperm midpiece. [provided by Alliance of Genome Resources, Apr 2022]

MT-RNR2 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 5 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000386347.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

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

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-TL1	ENST00000386347.1	TSL:6	n.22A>G		non_coding_transcript_exon	Exon 1 of 1
	MT-ND1	ENST00000361390.2	TSL:6	c.-56A>G		upstream_gene	N/A	ENSP00000354687.2	P03886
	MT-RNR2	ENST00000387347.2	TSL:6	n.*22A>G		downstream_gene	N/A

Frequencies

Mitomap GenBank AF: 0.0 AC: 0

Alfa AF: 0.00 Hom.: 0

Mitomap

Disease(s): MM-/-MELAS-with-chorea-ballism

Status: Reported

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	MELAS syndrome (2)
1	-	-	Mitochondrial disease (1)
1	-	-	Progressive external ophthalmoplegia, proximal myopathy, and sudden death (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	12
Hmtvar	Pathogenic	0.75
PhyloP100		0.91

Other links and lift over

dbSNP: rs199474662; hg19: chrM-3252;