rs118192101

Positions:

• chrM-8313-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 5 ACMG points: 5P and 0B. PP3 PM2_Supporting PS4_Supporting PS3_Supporting PM6_Supporting

This summary comes from the ClinGen Evidence Repository: The m.8313G>A variant in MT-TK has been reported in two unrelated probands with primary mitochondrial disease (PS4_supporting). One of these individuals had a severe gastroenteropathy, peripheral neuropathy, seizures, dementia, ataxia, retinitis pigmentosa, deafness, and died by age 15 years (PMID:9380435). The other individual had onset in her 20s of myopathy, nasal speech and swallowing difficulty, peripheral neuropathy, ptosis, and osteoporosis. Her condition was progressive and after several years she was non-ambulatory, had bulbar failure, and required tracheostomy and tube feeding (PMID:19618438). In both individuals, the variant was heteroplasmic, ranging from 54% in fibroblasts to 74-82% in muscle. In one of the reported cases, the variant was reported de novo as it was absent in blood from the proband’s mother, maternal aunt, and two brothers (PMID:9380435), however no additional tissues were tested (including that blood in the proband was not tested) and technology performed at the time of publication would not detect low heteroplasmy levels of the variant. In the other case, multiple tissues from the mother were tested as was muscle from two healthy brothers and the variant was not detectable (PMID:19618438), confirming de novo occurrence (PM6_supporting). Of note, three additional unrelated probands in a large cohort of individuals with autism spectrum disorder were reported to have this variant (PMID:35778412), however additional clinical details were not provided and there was no evidence these individuals had other features of primary mitochondrial disease. There is one occurrence of this variant in population databases (MITOMAP GenBank sequences, 1/59,389 or 0.002%; absent in Helix dataset and gnomAD v3.1.2). Although there is one occurrence, the frequency is still low (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic (73.6 percentile) and HmtVAR predicts it to be pathogenic score of 0.85 (PP3). Several functional studies reported show the deleterious effects of this variant (PS3_supporting). A single fiber study (PMID:19618438) demonstrated higher levels of variant in COX-negative fibers (96.44%; n =10) than in COX-positive fibers (72.11%; n= 10; P<0.001). A cybrid study (PMID:12737626) showed that cybrids with high levels of the variant had severe respiratory chain defects, diminished O2 consumption, and translational defects. Furthermore, a 7000-fold loss of aminoacylation efficiency was reported (PMIDs: 15477393, 15100439). In summary, 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 consistent functional evidence of a severe deleterious effect across multiple assays. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on March 13, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PS4_supporting, PM2_supporting, PP3, PM6_supporting, PS3_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA254837/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-TK ENST00000387421.1 non_coding_transcript_exon
• Scores: Mitotip Uncertain 16
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 MNGIE-like-/-Progressive-mito-cytopathy
• Conservation: PhyloP100: 7.31

Genes affected

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

TRNK (HGNC:):

MT-CO2 (HGNC:7421): (mitochondrially encoded cytochrome c oxidase II) Contributes to cytochrome-c oxidase activity. Predicted to be involved in mitochondrial electron transport, cytochrome c to oxygen and positive regulation of vasoconstriction. Located in mitochondrial inner membrane. Part of respiratory chain complex IV. Biomarker of Huntington's disease and stomach cancer. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 5 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRNK	TRNK.1	n.19G>A		non_coding_transcript_exon_variant	1/1
COX2	COX2.1			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MT-TK	ENST00000387421.1	n.19G>A		non_coding_transcript_exon_variant	1/1
MT-CO2	ENST00000361739.1			downstream_gene_variant				P1

Frequencies

GnomAD4 exome Cov.: 0

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

Mitomap

MNGIE-like-/-Progressive-mito-cytopathy

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

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

Mar 13, 2023

The m.8313G>A variant in MT-TK has been reported in two unrelated probands with primary mitochondrial disease (PS4_supporting). One of these individuals had a severe gastroenteropathy, peripheral neuropathy, seizures, dementia, ataxia, retinitis pigmentosa, deafness, and died by age 15 years (PMID: 9380435). The other individual had onset in her 20s of myopathy, nasal speech and swallowing difficulty, peripheral neuropathy, ptosis, and osteoporosis. Her condition was progressive and after several years she was non-ambulatory, had bulbar failure, and required tracheostomy and tube feeding (PMID: 19618438). In both individuals, the variant was heteroplasmic, ranging from 54% in fibroblasts to 74-82% in muscle. In one of the reported cases, the variant was reported de novo as it was absent in blood from the proband’s mother, maternal aunt, and two brothers (PMID: 9380435), however no additional tissues were tested (including that blood in the proband was not tested) and technology performed at the time of publication would not detect low heteroplasmy levels of the variant. In the other case, multiple tissues from the mother were tested as was muscle from two healthy brothers and the variant was not detectable (PMID: 19618438), confirming de novo occurrence (PM6_supporting). Of note, three additional unrelated probands in a large cohort of individuals with autism spectrum disorder were reported to have this variant (PMID: 35778412), however additional clinical details were not provided and there was no evidence these individuals had other features of primary mitochondrial disease. There is one occurrence of this variant in population databases (MITOMAP GenBank sequences, 1/59,389 or 0.002%; absent in Helix dataset and gnomAD v3.1.2). Although there is one occurrence, the frequency is still low (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic (73.6 percentile) and HmtVAR predicts it to be pathogenic score of 0.85 (PP3). Several functional studies reported show the deleterious effects of this variant (PS3_supporting). A single fiber study (PMID: 19618438) demonstrated higher levels of variant in COX-negative fibers (96.44%; n =10) than in COX-positive fibers (72.11%; n= 10; P<0.001). A cybrid study (PMID: 12737626) showed that cybrids with high levels of the variant had severe respiratory chain defects, diminished O2 consumption, and translational defects. Furthermore, a 7000-fold loss of aminoacylation efficiency was reported (PMIDs: 15477393, 15100439). In summary, 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 consistent functional evidence of a severe deleterious effect across multiple assays. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on March 13, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PM2_supporting, PP3, PM6_supporting, PS3_supporting. -

Mitochondrial DNA depletion syndrome 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 1997

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	16
Hmtvar	Pathogenic	0.85

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs118192101; hg19: chrM-8314;