chrM-3252-A-G

Variant names:

• chrM-3252-A-G
• rs199474661
• unassigned_transcript_4788:c.23A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PS4_Moderate PS2_Supporting PP1_Moderate PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.3252A>G variant in MT-TL1 has been reported in five unrelated families with primary mitochondrial disease (PS4_moderate). Some affected individuals had features consistent with myoclonic epilepsy with ragged red fibers (MERRF) and/or mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). Other manifestations include intellectual disability, pigmentary retinopathy, diabetes, dementia, renal failure, heart block, and hypoparathyroidism; and muscle biopsies showed ragged red fibers and complex I deficiency. Heteroplasmy levels ranged from 18% to greater than 90% in affected individuals (PMID:8111377; of note, two cases were included in manuscripts without a PMID:Seed et al., 2021, Tan et al., 2023; and two cases were provided by Expert Panel members). The variant segregated with disease manifestations in two families (PP1_moderate). In one, the proband had MELAS and had the variant present at 30% heteroplasmy in blood, 19% in lymphoblasts, and 76% in muscle. The mother had progressive generalized weakness, spastic paraparesis, and dysarthria onset in her 40s and died at 58 years following a stroke-like episode, and was found to have the variant present at 50% heteroplasmy in muscle (PMID:8111377). In one of the cases provided by an Expert Panel member, the proband had the variant present at >90% heteroplasmy. The less severely affected mother had the variant present at 55% in urine, 40% in buccal, and 18% in blood. The variant was present in the maternal grandmother at 19% in buccal sample, and at lower heteroplasmy levels in a maternal uncle with hearing loss. This variant occurred de novo in one of the reported individuals (absent in blood from mother; PS2_supporting, Tan et al., 2023). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic and HmtVAR predicts it to be pathogenic score of 0.5 (PP3). There are no cybrids, single fiber studies, or other functional assays reported on this variant. 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 September 9, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PS4_moderate, PP1_moderate, PS2_supporting, PM2_supporting, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120564/MONDO:0044970/015

• Frequency: Mitomap GenBank: Absent
• Consequence: TRNL1 unassigned_transcript_4788 missense
• Scores: Mitotip Uncertain 11
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3 O:1 MELAS,EXIT
• Conservation: PhyloP100: 6.99
• 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 7 ACMG points.

• PS2: 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.
• 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.23A>G	p.Asn8Ser	missense_variant	Exon 1 of 1
ND1	unassigned_transcript_4789	c.-55A>G		upstream_gene_variant
RNR2	unassigned_transcript_4787	n.*23A>G		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-TL1	ENST00000386347.1	n.23A>G		non_coding_transcript_exon_variant	Exon 1 of 1	6
MT-ND1	ENST00000361390.2	c.-55A>G		upstream_gene_variant		6		ENSP00000354687.2
MT-RNR2	ENST00000387347.2	n.*23A>G		downstream_gene_variant		6

Frequencies

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

Alfa AF: 0.00 Hom.: 0

Mitomap

Disease(s): MELAS,EXIT

Status: Reported,Reported

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

MELAS syndrome Pathogenic:1 Other:1

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.3252A>G 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: PM8, PM9, PM10 -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Mitochondrial disease Pathogenic:1

Sep 09, 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.3252A>G variant in MT-TL1 has been reported in five unrelated families with primary mitochondrial disease (PS4_moderate). Some affected individuals had features consistent with myoclonic epilepsy with ragged red fibers (MERRF) and/or mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). Other manifestations include intellectual disability, pigmentary retinopathy, diabetes, dementia, renal failure, heart block, and hypoparathyroidism; and muscle biopsies showed ragged red fibers and complex I deficiency. Heteroplasmy levels ranged from 18% to greater than 90% in affected individuals (PMID: 8111377; of note, two cases were included in manuscripts without a PMID: Seed et al., 2021, Tan et al., 2023; and two cases were provided by Expert Panel members). The variant segregated with disease manifestations in two families (PP1_moderate). In one, the proband had MELAS and had the variant present at 30% heteroplasmy in blood, 19% in lymphoblasts, and 76% in muscle. The mother had progressive generalized weakness, spastic paraparesis, and dysarthria onset in her 40s and died at 58 years following a stroke-like episode, and was found to have the variant present at 50% heteroplasmy in muscle (PMID: 8111377). In one of the cases provided by an Expert Panel member, the proband had the variant present at >90% heteroplasmy. The less severely affected mother had the variant present at 55% in urine, 40% in buccal, and 18% in blood. The variant was present in the maternal grandmother at 19% in buccal sample, and at lower heteroplasmy levels in a maternal uncle with hearing loss. This variant occurred de novo in one of the reported individuals (absent in blood from mother; PS2_supporting, Tan et al., 2023). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic and HmtVAR predicts it to be pathogenic score of 0.5 (PP3). There are no cybrids, single fiber studies, or other functional assays reported on this variant. 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 September 9, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PP1_moderate, PS2_supporting, PM2_supporting, PP3. -

Mitochondrial encephalomyopathy Pathogenic:1

Dec 01, 1993

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	11
Hmtvar	Pathogenic	0.50
PhyloP100		7.0

Other links and lift over

dbSNP: rs199474661; hg19: chrM-3253;