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
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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

PS4_Moderate PS3_Supporting PM5_Supporting PM2_Supporting PP3 PP1

PS2 PP4 PM6

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.

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).

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).

PM2_Supporting

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

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).

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

PM6

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

Curation History

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