M-616-T-C

Variant names:

• chrM-616-T-C
• rs387906420
• unassigned_transcript_4784:c.40T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PS4_Moderate PP1_Moderate PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.616T>C variant in MT-TF has been reported in at least 12 individuals from six families with features of a primary mitochondrial disease. Affected individuals had variable ages of onset (first few months of life with delays or seizures at 10 months old to late teenage years with renal disease or epilepsy). Several individuals had chronic kidney disease or renal failure; some even had transplants with non-recurrence of disease post-transplant. Other symptoms reported include developmental delay, epilepsy, status epilepticus (EPC), and myoclonus. Muscle biopsy revealed COX negative fibers. Heteroplasmy levels were the same in all affected probands as the variant was present at homoplasmy or > 97% in all tissues. Of note, some healthy family members had the variant at lower heteroplasmy levels but in at least one healthy family member, the variant was present at a heteroplasmy level as high as 92% (PS4_moderate; PMIDs: 31722346, 28267784, 20142618). There are no reports of de novo occurrence of this variant. This variant segregated with disease in multiple affected members in multiple families and several healthy family members had lower or undetectable levels of the variant (PP1_moderate; PMIDs: 31722346, 28267784, 20142618). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). There is one cybrid study for this variant however the cybrid also had another mtDNA variant precluding scoring for PS3. There are no single fiber studies or other functional assays reported for this variant. The computational predictor MitoTIP suggests this variant is pathogenic (83.3 percentile) and HmtVAR predicts it to be pathogenic score of 0.5 (PP3). 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 Mitochondrial Disease Variant Curation Expert Panel on June 13, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PS4_moderate, PP1_moderate, PP3, PM2_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120552/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: TRNF unassigned_transcript_4784 missense
• Scores: Mitotip Pathogenic 17
• Clinical Significance: Likely pathogenic reviewed by expert panel P:5 Maternally-inherited-epilepsy-/-mito-tubulointerstitial-kidney-disease-(MITKD)-/-Gitelman-like-syndrome,Maternally-inherited-epilepsy
• Conservation: PhyloP100: 3.71
• Publications: 1 publications found

Genes affected

TRNF (HGNC:7481): (mitochondrially encoded tRNA phenylalanine)

MT-RNR1 (HGNC:7470): (mitochondrially encoded 12S RNA) Enables DNA binding activity and DNA-binding transcription factor binding activity. Involved in several processes, including osteoblast proliferation; regulation of carbohydrate utilization; and regulation of phosphate metabolic process. Located in extracellular space; mitochondrion; and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

MT-RNR1 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 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.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000387314.1. 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-TF	ENST00000387314.1	TSL:6	n.40T>C		non_coding_transcript_exon	Exon 1 of 1
	MT-RNR1	ENST00000389680.2	TSL:6	n.-32T>C		upstream_gene	N/A

Frequencies

Mitomap GenBank The variant is not present, suggesting it is rare .

Mitomap

Disease(s): Maternally-inherited-epilepsy-/-mito-tubulointerstitial-kidney-disease-(MITKD)-/-Gitelman-like-syndrome,Maternally-inherited-epilepsy

Status: Cfrm-[LP],Reported

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	Mitochondrial disease (2)
1	-	-	Epilepsy, mitochondrial (1)
1	-	-	Interstitial nephritis (1)
1	-	-	MELAS syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Mitotip	Pathogenic	17
Hmtvar	Pathogenic	0.50
PhyloP100		3.7

Other links and lift over

dbSNP: rs387906420; hg19: chrM-618;