rs199476137

Positions:

• chrM-9203-CAT-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

Variant has been reported in ClinVar as Likely pathogenic (★★★).

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

Genes affected

ATP6 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very low frequency in mitomap database: 0.0
• PP5: Variant M-9203-CAT-C is Pathogenic according to our data. Variant chrM-9203-CAT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9646.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP6	unassigned_transcript_4806	c.679_680delTA	p.Ter227fs	frameshift_variant, stop_lost, splice_region_variant	1/1
COX3	unassigned_transcript_4807	c.-3_-2delAT		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt

Frequencies

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

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

Mitomap GenBank AF: 0.0 AC: 0

Mitomap

Encephalopathy-/-Seizures-/-Lacticacidemia

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial disease Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

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

Jun 30, 2022

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. -

Seizures and lactic acidosis Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 15, 2003

- -

Leber optic atrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

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: rs199476137; hg19: chrM-9204;