M-8340-G-A

Position:

• chrM-8340-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The ENST00000387421.1(MT-TK):​n.46G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★★★).

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-TK ENST00000387421.1 non_coding_transcript_exon
• Scores: Mitotip Uncertain 15
• Clinical Significance: Likely pathogenic reviewed by expert panel P:1 Myopathy+-Exercise-Intolerance+-CPEO-like-/childhood-epilepsy-with-SNHL-&-eye-disease
• Conservation: PhyloP100: 1.38

Genes affected

MT-TK (HGNC:7489): (mitochondrially encoded tRNA lysine)

TRNK (HGNC:):

MT-ATP8 (HGNC:7415): (mitochondrially encoded ATP synthase 8) 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 multiple sclerosis and urinary bladder cancer. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: No frequency data in Mitomap. Probably very rare.
• PP3: Mitotip and hmtvar scores support pathogenic criterium.
• PP5: Variant M-8340-G-A is Pathogenic according to our data. Variant chrM-8340-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 986424.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRNK	TRNK.1	n.46G>A		non_coding_transcript_exon_variant	1/1
ATP8	ATP8.1			upstream_gene_variant			YP_003024030.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MT-TK	ENST00000387421.1	n.46G>A		non_coding_transcript_exon_variant	1/1
MT-ATP8	ENST00000361851.1			upstream_gene_variant				ENSP00000355265	P1

Frequencies

GnomAD4 exome Cov.: 0

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

Mitomap

Myopathy+-Exercise-Intolerance+-CPEO-like-/childhood-epilepsy-with-SNHL-&-eye-disease

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

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

May 22, 2023

The m.8340G>A variant in MT-TK has been reported in five unrelated individuals with features of primary mitochondrial disease (PS4_moderate; PMIDs: 24161205, 29501485, 28729369, 36999085, 34969639). Affected individuals were variably affected and had myopathy, exercise intolerance, muscle weakness, and chronic progressive external ophthalmoplegia (CPEO). Additional features seen include sensorineural hearing loss, retinal dystrophy, cataracts, migraines, epilepsy, microcephaly, and poor growth, and one individual was reported to have congenital heart disease and urinary tract anomalies. There are at least three de novo occurrences reported in the literature (PM6; PMIDs: 29501485, 28729369, 24161205). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic (65th percentile) and HmtVAR predicts it to be pathogenic score of 0.4 (PP3). Single fiber testing showed higher levels of the variant in COX-deficient fibers (93.1% ± 0.26%, N=17) than in COX-positive fibers (29.5% ± 8.97, N=16), p<0.0001 (PS3_supporting, PMID: 28729369). 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 May 22, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PM6, PM2_supporting, PP3, PS3_supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	15
Hmtvar	Pathogenic	0.40

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrM-8341;