Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NC_012920.1:m.1644G>A

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA913163370

689846 (ClinVar)

Gene: MT-TV

Condition: mitochondrial disease

Inheritance Mode: Mitochondrial inheritance

Link to MONDO

UUID: 6b048e03-5584-4f4d-9f7b-eedc61d64cdc

Approved on: 2021-12-10

Published on: 2021-12-10

HGVS expressions

NC_012920.1:m.1644G>A

J01415.2:m.1644G>A

Likely Pathogenic

PP3 PP1 PS4_Moderate PM2_Supporting PS3_Supporting PM5_Supporting

PM6 PS2 PP4

Evidence Links 0

Expert Panel

Mitochondrial Diseases VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Mitochondrial Diseases VCEP

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.

PP3

The computational predictor MitoTIP suggests this variant impacts the function of this tRNA, as does HmtVar with a score of 1 (PP3).

PP1

This variant heteroplasmy level segregated with severity in 2 family members from 1 family (PP1; PMID: 15320572).

PS4_Moderate

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).

PM2_Supporting

This variant is absent in the GenBank data set and gnomAD v3.1.2 (PM2_supporting; queried 6/29/2020).

PS3_Supporting

Cybrid studies supported the functional impact of this variant (PS3_supporting; PMID: 24691472). See table 3 – all VCEP criteria met for cybrids [1 - biochemical deficiency must be observed in patient cell line with mtDNA variant in question: a significant combined respiratory complex defect was seen in Patient 3 fibroblasts (decrease in complex I and IV); 2 - whether the biochemical deficiency is transferred to mutant cybrids: Cybrids had profound defect of respiration and ATP synthesis, and low complex IV activity; 3 - cybrid cells carry high mutant load (minimal 60%): 100% m.1644G>A variant; not yet done in cells from another patient]; single-fiber testing also performed on muscle from Patient 2 and showed higher heteroplasmy levels (92 ±16%, n = 16) in COX negative fibers than fibers with normal COX activity (73 ± 28%, n =9,with p= 0.048).

PM5_Supporting

This variant is located at the same position as another pathogenic variant, m.1644G>T (PM5_supporting).

PM6

All variants reported to date have been inherited or family members were unavailable for testing

PS2

All variants reported to date have been inherited or family members were unavailable for testing

PP4

ETC testing not performed in CLIA/CAP/other certified lab as required per Mito VCEP specifications

Curation History

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.