Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • The variant label for this record ("m.6328C>T") 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: MT-CO1 CSPEC Genes: [] * Message MONDOs: MONDO:0044970 CSPEC MONDO: []
  • No CSPEC computed assertion could be determined for this classification!

Variant: m.6328C>T

CA120615

9671 (ClinVar)

Gene: MT-CO1
Condition: mitochondrial disease
Inheritance Mode: Mitochondrial inheritance
Link to MONDO
UUID: b4d09ff8-2a3f-4efa-9497-5ad14008c747
Approved on: 2023-12-21
Published on: 2024-11-26

HGVS expressions

NC_012920.1:m.6328C>T
J01415.2:m.6328C>T
ENST00000361624.2:c.425C>T

Uncertain Significance

Met criteria codes 3
PS3_Supporting PM2_Supporting PP3
Not Met criteria codes 1
PS4

Evidence Links 0

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.6328C>T (p.S142F) variant in MT-CO1 has been reported in one individual to date with primary mitochondrial disease. This individual had a severe cardioencephalomyopathy resembling mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) and harbored the variant at >95% heteroplasmy in muscle (PMID: 16284789). P. denitrificans models support a deleterious functional impact of this variant (PS3_supporting; PMID: 16284789). The computational predictors APOGEE1 and APOGEE2 give a consensus rating of pathogenic and each had a raw score of 0.90 (Min=0, Max=1), which predict a damaging effect on gene function (PP3). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). In summary, this variant meets criteria to be classified as uncertain significance 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 December 21, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS3_supporting, PM2_supporting, PP3.
Met criteria codes
PS3_Supporting
P. denitrificans models support a deleterious functional impact of this variant (PS3_supporting; PMID: 16284789).
PM2_Supporting
This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting).
PP3
The computational predictors APOGEE1 and APOGEE2 give a consensus rating of pathogenic and each had a raw score of 0.90 (Min=0, Max=1), which predict a damaging effect on gene function (PP3).
Not Met criteria codes
PS4
The m.6328C>T (p.Ser142Phe) variant in MT-CO1 has been reported in one individual to date with primary mitochondrial disease. This individual had a severe cardioencephalomyopathy resembling MELAS and harbored the variant at >95% heteroplasmy in muscle. This does not meet criteria for PS4_supporting which requires at least two unrelated affected individuals (PS4_supporting not met; PMID: 16284789).
Curation History
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