The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • There was no gene found in the curated document received from the VCI/VCEP
  • The variant label for this record ("m.9537dupC") does not appear to be in HGVS format
  • Despite there being a valid 'cspec' property in the messages there's a discrepancy in message contents and CSPEC data: * Message Gene: undefined CSPEC Genes: [] * Message MONDOs: MONDO:0044970 CSPEC MONDO: []
  • No CSPEC computed assertion could be determined for this classification!


Variant: m.9537dupC

CA120602

9656 (ClinVar)

Gene: N/A
Condition: mitochondrial disease
Inheritance Mode: Mitochondrial inheritance
UUID: 74807869-0714-43e3-b9c9-bb500bca4635
Approved on: 2024-04-22
Published on: 2024-12-11

HGVS expressions

NC_012920.1:m.9537dup
J01415.2:m.9537dup
ENST00000362079.2:c.331dup

Likely Pathogenic

Met criteria codes 3
PM2_Supporting PS3_Supporting PVS1_Strong
Not Met criteria codes 2
PS4 PP3

Evidence Links 2

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Mitochondrial Disease Nuclear and Mitochondrial Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1_mtDNA

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Mitochondrial Diseases VCEP
The m.9537dupC variant in MT-CO3 has been reported in one individual with primary mitochondrial disease to date (PMID: 11063732), in an 11-year-old girl with Leigh syndrome spectrum disorder. Progressive spastic paraparesis, ophthalmoplegia, and moderate intellectual disability were noted at age four years, as was severe lactic acidosis and lesions in the putamina on brain imaging. The variant was reported as being “virtually homoplasmic” in skeletal muscle, fibroblasts, and lymphocytes. The variant was not detected in lymphocytes from her unaffected brother and maternal grandmother, and was similarly absent in lymphocytes, hair, and oral epithelial cells in her mother. However, technology at the time was limited in detecting low heteroplasmy levels. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). There are no in silico predictors for this type of variant in mitochondrial DNA. This frameshift variant at amino position 111 creates a stop codon three positions downstream, resulting in a significant (57%) truncation of the MT-CO3 protein (PVS1_strong). Cybrid studies supported the functional impact of this variant (PMID: 11063732), as did studies in colonic crypt stem cells (PMID: 14597761; PS3_supporting). 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 April 22, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PVS1_strong, PM2_supporting, PS3_supporting.
Met criteria codes
PM2_Supporting
This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting).
PS3_Supporting
100% mutant cybrid cell line showed a profound isolated COX defect (PMID 11063732).No full-length COX III protein was detected in these cells using in vivo mtDNA translation assays. Western blot analysis of 2D blue-native electrophoresis showed that the fully assembled COX complex was absent in the cybrids. Additionally, there was reduction of specific cross-reacting material and the accumulation of early-assembly intermediates of COX. In another study (PMID 14597761), colonic stem cells were used to demonstrate a COX deficiency in individual crypts carrying homoplasmic m,9537Cdup.

PVS1_Strong
The duplication at base position 9537 causes a frame-shift at codon 111, creating a STOP only 3 positions downstream. This causes a significant truncation (57%) of the CO3 protein.
Not Met criteria codes
PS4
The MT-CO3 m.9537dupC variant has been reported in one patient, 11-year-old girl with a negative family history, with Leigh-like syndrome (Tiranti 2000 PMID 11063732 ). The homoplasmic variant m.9537dupC was found in both patient muscle and skin biopsy samples. It has also been reported in colonic crypt stem cells in a study of aging tissues (Taylor 2004 PMID 14597761).
PP3
No appropriate in-silico tools are currently available for prediction of pathogenicity for duplications or deletions.
Curation History
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