rs199474666

Variant names:

• chrM-3274-A-G
• rs199474666
• unassigned_transcript_4788:c.45A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PS3_Supporting PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.3274A>G in MT-TL1 has been reported in one individual to date, in a man with a progressive neuropsychiatric disorder and multisystem organ involvement. At 12 years old, he had a decline in school performance. By his late 20s, he experienced acute psychotic symptoms and depression. He also had bilateral hearing loss, gait instability, and bilateral dysdiadokinesis. By his early 30s, he had cataracts, retinal degeneration, muscle weakness, ataxic gait, dysarthria, intention tremor, and dysmetria. Brain MRIs showed progressive cerebral and cerebellar atrophy and T2 hyperintense lesions in the basal ganglia. He had elevated blood and cerebrospinal fluid lactate. Muscle biopsy showed increased central nuclei and ragged red fibers, with reduced complex I activity (53% of lowest norm). The variant was present at 25% in muscle and undetectable in blood (PMID:11723298). The variant was absent in blood from three healthy maternal family members, but this cannot be considered evidence of de novo status as the variant was also absent in the proband’s blood. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Single fiber testing showed higher levels of the variant in ragged red fibers (55 ± 26.1%; N=22; mutant mtDNA found in every fiber) than in normal fibers (14 ± 25.7%; N=16; mutant mtDNA found in 7/16 fibers), p<0.001 (PS3_supporting, PMID:11723298). The computational predictor MitoTIP suggests this variant is pathogenic (77.1 percentile) and HmtVAR predicts it to be pathogenic score of 0.55 (PP3). In summary, this variant meets criteria to be classified as uncertain significance 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 April 23, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PS3_supporting, PM2_supporting, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120568/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: TRNL1 unassigned_transcript_4788 synonymous
• Scores: Mitotip Pathogenic 16
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:2 Neuropsychiatric-syndrome-+-cataract
• Conservation: PhyloP100: 0.987
• 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: Uncertain_significance. The variant received 3 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.
• PP3: 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.45A>G	p.Leu15Leu	synonymous_variant	Exon 1 of 1
ND1	unassigned_transcript_4789	c.-33A>G		upstream_gene_variant
RNR2	unassigned_transcript_4787	n.*45A>G		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-TL1	ENST00000386347.1	n.45A>G		non_coding_transcript_exon_variant	Exon 1 of 1	6
MT-ND1	ENST00000361390.2	c.-33A>G		upstream_gene_variant		6		ENSP00000354687.2
MT-RNR2	ENST00000387347.2	n.*45A>G		downstream_gene_variant		6

Frequencies

Mitomap GenBank The variant is not present, suggesting it is rare .

Alfa AF: 0.000151 Hom.: 1

Mitomap

Disease(s): Neuropsychiatric-syndrome-+-cataract

Status: Reported

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Neuropsychiatric disorder and early-onset cataract Pathogenic:1

Nov 27, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

MELAS syndrome Pathogenic:1

Jul 12, 2019

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NC_012920.1:m.3274A>G variant in MT-TL1 gene is interpreted to be a Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes reported in the guidelines: PS3, PM7, PM8, PM9 -

MERRF syndrome Uncertain:1

Aug 23, 2022

MGZ Medical Genetics Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mitochondrial disease Uncertain:1

Apr 23, 2024

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

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The m.3274A>G in MT-TL1 has been reported in one individual to date, in a man with a progressive neuropsychiatric disorder and multisystem organ involvement. At 12 years old, he had a decline in school performance. By his late 20s, he experienced acute psychotic symptoms and depression. He also had bilateral hearing loss, gait instability, and bilateral dysdiadokinesis. By his early 30s, he had cataracts, retinal degeneration, muscle weakness, ataxic gait, dysarthria, intention tremor, and dysmetria. Brain MRIs showed progressive cerebral and cerebellar atrophy and T2 hyperintense lesions in the basal ganglia. He had elevated blood and cerebrospinal fluid lactate. Muscle biopsy showed increased central nuclei and ragged red fibers, with reduced complex I activity (53% of lowest norm). The variant was present at 25% in muscle and undetectable in blood (PMID: 11723298). The variant was absent in blood from three healthy maternal family members, but this cannot be considered evidence of de novo status as the variant was also absent in the proband’s blood. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Single fiber testing showed higher levels of the variant in ragged red fibers (55 ± 26.1%; N=22; mutant mtDNA found in every fiber) than in normal fibers (14 ± 25.7%; N=16; mutant mtDNA found in 7/16 fibers), p<0.001 (PS3_supporting, PMID: 11723298). The computational predictor MitoTIP suggests this variant is pathogenic (77.1 percentile) and HmtVAR predicts it to be pathogenic score of 0.55 (PP3). In summary, this variant meets criteria to be classified as uncertain significance 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 April 23, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS3_supporting, PM2_supporting, PP3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Pathogenic	16
Hmtvar	Pathogenic	0.55
PhyloP100		0.99

Other links and lift over

dbSNP: rs199474666; hg19: chrM-3275;