rs193303018

Variant names:

• chrM-3242-G-A
• rs193303018
• unassigned_transcript_4788:c.13G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PS4_Moderate PM6_Supporting PS3_Moderate PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.3242G>A variant in MT-TL1 has been reported in at least six unrelated individuals with primary mitochondrial disease (PMIDs: 15870203, 19460299, 10214753, 21364701, 14576046, 22781753, 24667782, 31965079, 37038312; PS4_moderate). Clinical features in affected individuals include Leigh syndrome spectrum disorder, encephalomyopathy, myopathy, hypertrophic and dilated cardiomyopathy, and renal insufficiency. The variant occurred de novo in two of these individuals (PMID:22781753; PM6_supporting). There are no families reported where the variant segregated with clinical manifestations. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). In silico predictors are conflicting as the computational predictor MitoTIP suggests this variant is likely benign (18.5 percentile) but HmtVAR predicts it to be possibly pathogenic with a score of 0.6. A cybrid study (PMID:19460299) from cells derived from the index case (PMID:15870203) demonstrated reduced activity of complex IV. Additional studies showed this variant eliminated transcriptional termination activity with a modest decrease (30%–50%) of mtRNase P activity (PMID:20550934), and that this variant was associated with decreased single-turnover methyltransferase and cleavage activity of human mitochondrial mtRNase P (PS3_moderate). 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 November 11, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PS4_moderate, PS3_moderate, PM2_supporting, PM6_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA280144/MONDO:0044970/015

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 0)
• Consequence: TRNL1 unassigned_transcript_4788 missense
• Scores: Mitotip Benign 7.0
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4 MM-/-HCM+renal-tubular-dysfunction
• Conservation: PhyloP100: 4.54
• Publications: 3 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 6 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.
• PM6: 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

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-TL1	ENST00000386347.1	TSL:6	n.13G>A		non_coding_transcript_exon	Exon 1 of 1
	MT-ND1	ENST00000361390.2	TSL:6	c.-65G>A		upstream_gene	N/A	ENSP00000354687.2
	MT-RNR2	ENST00000387347.2	TSL:6	n.*13G>A		downstream_gene	N/A

Frequencies

Mitomap GenBank AF: 0.0 AC: 0

Alfa AF: 0.00 Hom.: 0

Mitomap

Disease(s): MM-/-HCM+renal-tubular-dysfunction

Status: Reported

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	MELAS syndrome (2)
1	-	-	Mitochondrial disease (1)
1	-	-	Myelodysplastic syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Mitotip	Benign	7.0
Hmtvar	Pathogenic	0.60
PhyloP100		4.5

Other links and lift over

dbSNP: rs193303018; hg19: chrM-3243;