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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRNL1	unassigned_transcript_4788	c.13G>A	p.Glu5Lys	missense_variant	Exon 1 of 1
ND1	unassigned_transcript_4789	c.-65G>A		upstream_gene_variant
RNR2	unassigned_transcript_4787	n.*13G>A		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-TL1	ENST00000386347.1	n.13G>A		non_coding_transcript_exon_variant	Exon 1 of 1	6
MT-ND1	ENST00000361390.2	c.-65G>A		upstream_gene_variant		6		ENSP00000354687.2
MT-RNR2	ENST00000387347.2	n.*13G>A		downstream_gene_variant		6

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

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

MELAS syndrome Pathogenic:2

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 12, 2019

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NC_012920.1:m.3242G>A variant in MT-TL1 gene is interpreted to be a Likely Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes reported in the guidelines: PS5, PM9, PM10 -

Myelodysplastic syndrome Pathogenic:1

Jun 11, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mitochondrial disease Pathogenic:1

Nov 11, 2024

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

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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. -

Computational scores

Source: dbNSFP v4.3

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;