M-1644-G-A

Position:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PP1PP3PS4_ModeratePS3_SupportingPM5_SupportingPM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.1644G>A variant in MT-TV was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel as part of the variant pilot for mitochondrial DNA variant specifications (McCormick et al., 2020; PMID:32906214). This variant has been reported in 7 individuals with primary mitochondrial disease with variable features including cardiac (hypertrophic cardiomyopathy, LBBB); neurologic (neurodegeneration/dementia, stroke-like episodes, recurrent encephalopathy, epilepsy, ataxia, dystonia, Parkinsonism, mood disorder/disturbances, fatigue, muscle weakness, exercise intolerance, neuropathy, cognitive impairment, developmental regression); audiologic (bilateral sensorineural hearing loss); renal (cystic renal disease); GI (severe GI dysmotility, cachexia); and endocrine (diabetes) concerns as well as lab abnormalities (elevated blood and CSF lactate, elevated CK), and brain imaging abnormalities (atrophy, basal ganglia lesions, MRS lactate peak); with heteroplasmy levels in multiple tissues ranging from 85% to homoplasmy (PS4; PMIDs: 15320572, 23847141, 18314141, 21986556, 24691472). This variant heteroplasmy level segregated with severity in 2 family members from 1 family (PP1; PMID:15320572). This variant is located at the same position as another variant associated with mitochondrial disease, m.1644G>T (PM5_supporting). This variant is absent in the GenBank data set and gnomAD v3.1.2 (PM2_supporting). The computational predictor MitoTIP suggests this variant impacts the function of this tRNA, as does HmtVar with a score of 1 (PP3). Cybrid studies supported the functional impact of this variant (PS3_supporting; PMID:24691472). 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 U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel as of August 20, 2020. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS4, PS3_supporting, PM2_supporting, PM5_supporting, PP1, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA913163370/MONDO:0044970/014

Frequency

Mitomap GenBank:
Absent

Consequence

MT-TV
ENST00000387342.1 non_coding_transcript_exon

Scores

Mitotip
Uncertain
13

Clinical Significance

Likely pathogenic reviewed by expert panel P:3O:1
Leigh-Syndrome-/-HCM-/-MELAS,Adult-Leigh-Syndrome

Conservation

PhyloP100: 0.980
Variant links:
Genes affected
MT-TV (HGNC:7500): (mitochondrially encoded tRNA valine)
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-RNR1 (HGNC:7470): (mitochondrially encoded 12S RNA) Enables DNA binding activity and DNA-binding transcription factor binding activity. Involved in several processes, including osteoblast proliferation; regulation of carbohydrate utilization; and regulation of phosphate metabolic process. Located in extracellular space; mitochondrion; and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PS3
PS4
PM2
PM5
PP1
PP3

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TRNVTRNV.1 use as main transcriptn.43G>A non_coding_transcript_exon_variant 1/1
RNR2RNR2.1 use as main transcript upstream_gene_variant
RNR1RNR1.1 use as main transcript downstream_gene_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MT-TVENST00000387342.1 linkuse as main transcriptn.43G>A non_coding_transcript_exon_variant 1/1
MT-RNR2ENST00000387347.2 linkuse as main transcript upstream_gene_variant
MT-RNR1ENST00000389680.2 linkuse as main transcript downstream_gene_variant

Frequencies

GnomAD4 exome
Cov.:
0
We have no GnomAD4 genomes data on this position. Probably position not covered by the project.
Gnomad homoplasmic
AF:
0.0
AC:
0
AN:
56431
Gnomad heteroplasmic
AF:
0.000018
AC:
1
AN:
56431

Mitomap

Leigh-Syndrome-/-HCM-/-MELAS,Adult-Leigh-Syndrome

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:3Other:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Juvenile myopathy, encephalopathy, lactic acidosis AND stroke Pathogenic:2Other:1
Pathogenic, criteria provided, single submitterclinical testingMendelicsMay 04, 2022- -
Pathogenic, criteria provided, single submitterclinical testingWong Mito Lab, Molecular and Human Genetics, Baylor College of MedicineJul 12, 2019The NC_012920.1:m.1644G>A variant in MT-TV 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, PP3 -
not provided, no classification providedliterature onlyGeneReviews-- -
Mitochondrial disease Pathogenic:1
Likely pathogenic, reviewed by expert panelcurationClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGenDec 10, 2021The m.1644G>A variant in MT-TV was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel as part of the variant pilot for mitochondrial DNA variant specifications (McCormick et al., 2020; PMID: 32906214). This variant has been reported in 7 individuals with primary mitochondrial disease with variable features including cardiac (hypertrophic cardiomyopathy, LBBB); neurologic (neurodegeneration/dementia, stroke-like episodes, recurrent encephalopathy, epilepsy, ataxia, dystonia, Parkinsonism, mood disorder/disturbances, fatigue, muscle weakness, exercise intolerance, neuropathy, cognitive impairment, developmental regression); audiologic (bilateral sensorineural hearing loss); renal (cystic renal disease); GI (severe GI dysmotility, cachexia); and endocrine (diabetes) concerns as well as lab abnormalities (elevated blood and CSF lactate, elevated CK), and brain imaging abnormalities (atrophy, basal ganglia lesions, MRS lactate peak); with heteroplasmy levels in multiple tissues ranging from 85% to homoplasmy (PS4; PMIDs: 15320572, 23847141, 18314141, 21986556, 24691472). This variant heteroplasmy level segregated with severity in 2 family members from 1 family (PP1; PMID: 15320572). This variant is located at the same position as another variant associated with mitochondrial disease, m.1644G>T (PM5_supporting). This variant is absent in the GenBank data set and gnomAD v3.1.2 (PM2_supporting). The computational predictor MitoTIP suggests this variant impacts the function of this tRNA, as does HmtVar with a score of 1 (PP3). Cybrid studies supported the functional impact of this variant (PS3_supporting; PMID: 24691472). 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 U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel as of August 20, 2020. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS4, PS3_supporting, PM2_supporting, PM5_supporting, PP1, PP3. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
Mitotip
Uncertain
13
Hmtvar
Pathogenic
1.0

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs587776441; hg19: chrM-1646; API