rs199474659

Variant names:

• chrM-3256-C-T
• rs199474659
• unassigned_transcript_4788:c.27C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PS4_Moderate PS3_Supporting PP3 PP1 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.3256C>T variant in MT-TL1 has been reported in four individuals in the literature and an additional four cases were seen by experts on this panel. Affected individuals had primary mitochondrial disease with variable features including MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) phenotype, neurologic involvement (neurodegeneration/dementia, stroke-like episodes, recurrent encephalopathy, seizures, ataxia, myoclonus); neuromuscular involvement (muscle atrophy, progressive myopathy); cardiac involvement (cardiac failure); ophthalmologic involvement (ophthalmoplegia, ptosis, central vision loss); ENT involvement (hearing loss); endocrine involvement (hashimoto thyroiditis, diabetes mellitus); lab abnormalities (elevated blood and CSF lactate and pyruvate); and brain imaging findings (progressive brain atrophy); with heteroplasmy levels in multiple tissues ranging from 8% - 98% (PS4_moderate; PMIDs: 19941338, 10953207, 7804130, 8254046). This variant segregated with disease in a single reported family as the proband’s healthy sister had undetectable levels of variant in blood; the proband’s mother was decreased; and the proband was heteroplasmic for the variant in numerous tissues: 64% (muscle), 8% (white blood cells), 48% (first passage cultured fibroblasts), and 18% (hair roots) (PP1; PMID:8254046). There are no reports of de novo occurrences of this variant to our knowledge. Ragged red fiber (RRF) analysis in muscle noted only partially impaired COX activity. However, when analyzed for levels of mutant genomes, RRFs were essentially homoplasmic for mutant mtDNAs (range 94-97%). Normal (non-RRFs) had much lower levels of mutant genomes (34-75%). The percentage of mutant mtDNA in total the muscle was 64% (PS3_supporting: PMID:8254046). This variant is absent from Mitomap's 51,863 sequences (AF=0.00%); Helix's 196,554 sequences (AF=0.00%); and gnomAD v3.1.2 (PM2_supporting). The computational predictor MitoTIP suggests this variant impacts the function of this tRNA with a score of 93.70%, as does HmtVar with a score of 0.75 (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. We note that some experts on this panel voted for a classification of pathogenic given the overwhelming evidence of pathogenicity (strong single fiber studies, absent in population databases and present in eight individuals with features of primary mitochondrial disease). This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on August 8, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PS4_moderate, PM2_supporting, PP3, PP1, PS3_supporting LINK:https://erepo.genome.network/evrepo/ui/classification/CA120561/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: TRNL1 unassigned_transcript_4788 synonymous
• Scores: Mitotip Pathogenic 19
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4 O:1 MELAS|-possible-atherosclerosis-risk
• Conservation: PhyloP100: 1.96
• Publications: 4 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.
• 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.27C>T	p.Arg9Arg	synonymous_variant	Exon 1 of 1
ND1	unassigned_transcript_4789	c.-51C>T		upstream_gene_variant
RNR2	unassigned_transcript_4787	n.*27C>T		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-TL1	ENST00000386347.1	n.27C>T		non_coding_transcript_exon_variant	Exon 1 of 1	6
MT-ND1	ENST00000361390.2	c.-51C>T		upstream_gene_variant		6		ENSP00000354687.2
MT-RNR2	ENST00000387347.2	n.*27C>T		downstream_gene_variant		6

Frequencies

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

Mitomap

Disease(s): MELAS|-possible-atherosclerosis-risk

Status: Cfrm-[LP]

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

MELAS syndrome Pathogenic:1 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

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.3256C>T 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, PS5, PM7 -

MERRF syndrome Pathogenic:1

Mar 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mitochondrial disease Pathogenic:1

Aug 08, 2022

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.3256C>T variant in MT-TL1 has been reported in four individuals in the literature and an additional four cases were seen by experts on this panel. Affected individuals had primary mitochondrial disease with variable features including MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) phenotype, neurologic involvement (neurodegeneration/dementia, stroke-like episodes, recurrent encephalopathy, seizures, ataxia, myoclonus); neuromuscular involvement (muscle atrophy, progressive myopathy); cardiac involvement (cardiac failure); ophthalmologic involvement (ophthalmoplegia, ptosis, central vision loss); ENT involvement (hearing loss); endocrine involvement (hashimoto thyroiditis, diabetes mellitus); lab abnormalities (elevated blood and CSF lactate and pyruvate); and brain imaging findings (progressive brain atrophy); with heteroplasmy levels in multiple tissues ranging from 8% - 98% (PS4_moderate; PMIDs: 19941338, 10953207, 7804130, 8254046). This variant segregated with disease in a single reported family as the proband’s healthy sister had undetectable levels of variant in blood; the proband’s mother was decreased; and the proband was heteroplasmic for the variant in numerous tissues: 64% (muscle), 8% (white blood cells), 48% (first passage cultured fibroblasts), and 18% (hair roots) (PP1; PMID: 8254046). There are no reports of de novo occurrences of this variant to our knowledge. Ragged red fiber (RRF) analysis in muscle noted only partially impaired COX activity. However, when analyzed for levels of mutant genomes, RRFs were essentially homoplasmic for mutant mtDNAs (range 94-97%). Normal (non-RRFs) had much lower levels of mutant genomes (34-75%). The percentage of mutant mtDNA in total the muscle was 64% (PS3_supporting: PMID: 8254046). This variant is absent from Mitomap's 51,863 sequences (AF=0.00%); Helix's 196,554 sequences (AF=0.00%); and gnomAD v3.1.2 (PM2_supporting). The computational predictor MitoTIP suggests this variant impacts the function of this tRNA with a score of 93.70%, as does HmtVar with a score of 0.75 (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. We note that some experts on this panel voted for a classification of pathogenic given the overwhelming evidence of pathogenicity (strong single fiber studies, absent in population databases and present in eight individuals with features of primary mitochondrial disease). This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on August 8, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PM2_supporting, PP3, PP1, PS3_supporting -

Diabetes mellitus, noninsulin-dependent, maternally transmitted Pathogenic:1

Mar 01, 1998

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	Pathogenic	19
Hmtvar	Pathogenic	0.75
PhyloP100		2.0

Other links and lift over

dbSNP: rs199474659; hg19: chrM-3257;