rs199476137

Variant names:

• chrM-9203-CAT-C
• rs199476137
• ENST00000361899.2:c.679_680delTA

Variant summary

Our verdict is Likely pathogenic. The variant received 5 ACMG points: 5P and 0B. PM6_Supporting PM4 PM2_Supporting PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The m.9205_9206delTA (p.Ter227M) variant in MT-ATP6 has been reported in two unrelated probands with features of primary mitochondrial disease (neonatal lactic acidosis, failure to thrive, spasticity, microcephaly, developmental delay; PS4_supporting; PMIDs: 8739943, 15265003). The variant was de novo in one of these individuals (absent in mother and maternal grandmother's lymphocytes via PCR-SSCP; PM6_supporting; PMID:8739943). In the other family, this variant segregated with disease in two unaffected family members as they had lower levels of the variant, however the unaffected mother’s heteroplasmy level was still fairly high at >90% (PMID:15265003). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). There are no cybrids or single fiber studies reported on this variant. The loss residue removes the termination codon for MT-ATP6 and sets MT-CO3 immediately in frame. This results in decreased steady state level of RNA14, the ATPase 8- and 6-encoding bi-cistronic mRNA unit, causing dysregulation of mRNA stability (PM4, PMID:12915481). This variant meets criteria to be classified as uncertain significance however, after extensive discussion, this Expert Panel elected to modify the classification to likely pathogenic given the functional evidence showing destabilization of the RNA. In summary, this variant is classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PM6_supporting, PM2_supporting, PM4, PS4_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120599/MONDO:0044970/014

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 0)
• Consequence: MT-ATP6 ENST00000361899.2 frameshift, stop_lost, splice_region
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3 Encephalopathy-/-Seizures-/-Lacticacidemia
• Conservation: PhyloP100: 4.88
• Publications: 2 publications found

Genes affected

MT-ATP6 (HGNC:7414): (mitochondrially encoded ATP synthase 6) Contributes to proton-transporting ATP synthase activity, rotational mechanism. Involved in mitochondrial ATP synthesis coupled proton transport. Part of mitochondrial proton-transporting ATP synthase complex. Implicated in Leber hereditary optic neuropathy; NARP syndrome; Parkinson's disease; multiple sclerosis; and systemic lupus erythematosus. [provided by Alliance of Genome Resources, Apr 2022]

MT-CO3 (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]

MT-CO3 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• hereditary recurrent myoglobinuria

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• cytochrome-c oxidase deficiency disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Leber hereditary optic neuropathy

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome

  Inheritance: Mitochondrial Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 5 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM4: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000361899.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-ATP6	ENST00000361899.2	TSL:6	c.679_680delTA	p.Ter227fs	frameshift stop_lost splice_region	Exon 1 of 1	ENSP00000354632.2	P00846
	MT-CO3	ENST00000362079.2	TSL:6	c.-3_-2delAT		upstream_gene	N/A	ENSP00000354982.2	P00414

Frequencies

Mitomap GenBank AF: 0.0 AC: 0

Mitomap

Disease(s): Encephalopathy-/-Seizures-/-Lacticacidemia

Status: Cfrm-[LP]

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	Leber optic atrophy (1)
1	-	-	Mitochondrial disease (1)
1	-	-	Seizures and lactic acidosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.9

Other links and lift over

dbSNP: rs199476137; hg19: chrM-9204;