rs267606614

Variant names:

• chrM-9531-A-AC
• rs267606614
• unassigned_transcript_4806:c.331dupC

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Mitomap GenBank: Absent
• Consequence: COX3 frameshift
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 O:1 Leigh-Disease
• Conservation: PhyloP100: 7.62

Genes affected

COX3 (HGNC:7422): (mitochondrially encoded cytochrome c oxidase III) Predicted to enable electron transfer activity and oxidoreduction-driven active transmembrane transporter activity. Involved in respiratory chain complex IV assembly. Part of respiratory chain complex IV. Implicated in MELAS syndrome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: No frequency data in Mitomap. Probably very rare.
• PP5: Variant M-9531-A-AC is Pathogenic according to our data. Variant chrM-9531-A-AC is described in ClinVar as [Pathogenic]. Clinvar id is 9656.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COX3	unassigned_transcript_4806	c.331dupC	p.Gln111fs	frameshift_variant	Exon 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt

Frequencies

GnomAD4 exome Cov.: 0

We have no GnomAD4 genomes data on this position. Probably position not covered by the project.

Mitomap

Leigh-Disease

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial complex IV deficiency, nuclear type 1 Pathogenic:1

Nov 01, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Mitochondrial disease Pathogenic:1

Apr 22, 2024

ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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. -

Leigh syndrome Other:1

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs267606614; hg19: chrM-9532;