M-5814-T-C

Variant names:

• chrM-5814-T-C
• rs200077222
• unassigned_transcript_4797:c.13A>G

Variant summary

Our verdict is Likely benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The m.5814T>C variant in MT-TC was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel on June 26, 2023. This variant has been reported in several individuals with features of primary mitochondrial disease beginning in 1996. However, other genetic etiologies were not excluded due to technical limitations at the time and this variant is now recognized to be present at very high frequencies in population databases, especially in individuals in haplogroup L2. The variant was first reported in individuals with Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes (MELAS, PMID:8829635); progressive external ophthalmoplegia and encephalopathy (PMID:9185178); hypertrophic cardiomyopathy, myopathy, and lactic acidosis (PMID:11453453); exercise intolerance and ragged red fibers (PMID:11335700); and severe encephalopathy (PMID:17241783). The variant was present at >90% heteroplasmy to homoplasmy in all severely affected individuals. The variant was present at variable levels in family members of affected individuals, ranging from 8% to homoplasmy (PMIDs: 9185178, 11335700, 17241783). There are no reported de novo occurrences of the variant to our knowledge. Single fiber testing was performed however there was wide variability in the heteroplasmy level in normal and abnormal muscle fibers, as well as overlap in the heteroplasmy levels among normal and abnormal muscle fibers (PMID:8829635). This variant is present at high frequencies in population databases (BA1). The frequency in the MITOMAP GenBank sequences is 215/59,389 (0.362%) including in 132/133 individuals from haplogroup L2b and also seen in individuals from haplogroups R0, N, H4a, B4a, and others. The frequency in gnomAD v3.1.2 is 779/56,413 (1.377%) including 777 homoplasmic occurrences (seen across populations and haplogroups, highest in African/African Americans and L2) and two heteroplasmic occurrences, and seen in individuals across age groups. The frequency in Helix is 519/195,983 (0.255%) including 500 homoplasmic occurrences (seen across haplogroups, highest in L2) and 19 heteroplasmic occurrences. The computational predictor MitoTIP suggests this variant is benign (38.8 percentile) and HmtVAR predicts it to be pathogenic score of 0.75. In summary, this variant meets criteria to be classified as benign for primary mitochondrial disease inherited in a mitochondrial manner. This variant is associated with haplogroup L2 and therefore would not be associated with primary mitochondrial disease in individuals from this haplogroup. While this variant is seen across haplogroups, the effects of this variant in other haplogroups is not as well-defined. Furthermore, while single fiber testing showed differences in mean heteroplasmy levels in normal and abnormal muscle fibers, this did not provide definitive evidence of pathogenicity. However, taken together, this expert panel elected to modify the classification to likely benign. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on June 26, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied: BA1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA259739/MONDO:0044970/015

• Frequency: Mitomap GenBank: 𝑓 0.0036 (AC: 221)
• Consequence: TRNC unassigned_transcript_4797 missense
• Scores: Mitotip Uncertain 11
• Clinical Significance: Likely benign reviewed by expert panel P:1 U:1 B:2 Encephalopathy-/-gout
• Conservation: PhyloP100: 0.281
• Publications: 4 publications found

Genes affected

TRNC (HGNC:7477): (mitochondrially encoded tRNA cysteine)

MT-CO1 (HGNC:7419): (mitochondrially encoded cytochrome c oxidase I) Contributes to cytochrome-c oxidase activity. Predicted to be involved in electron transport coupled proton transport and mitochondrial electron transport, cytochrome c to oxygen. Part of mitochondrial respiratory chain complex III and mitochondrial respiratory chain complex IV. [provided by Alliance of Genome Resources, Apr 2022]

TRNN (HGNC:7493): (mitochondrially encoded tRNA asparagine)

TRNA (HGNC:7475): (mitochondrially encoded tRNA alanine)

TRNW (HGNC:7501): (mitochondrially encoded tRNA tryptophan)

TRNY (HGNC:7502): (mitochondrially encoded tRNA tyrosine)

TRNY Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -8 ACMG points.

• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000387405.1. 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-TC	ENST00000387405.1	TSL:6	n.13A>G		non_coding_transcript_exon	Exon 1 of 1
	MT-CO1	ENST00000361624.2	TSL:6	c.-90T>C		upstream_gene	N/A	ENSP00000354499.2	P00395
	MT-TA	ENST00000387392.1	TSL:6	n.-159A>G		upstream_gene	N/A

Frequencies

Mitomap GenBank AF: 0.0036 AC: 221

Gnomad homoplasmic AF: 0.014 AC: 777 AN: 56413

Gnomad heteroplasmic AF: 0.000035 AC: 2 AN: 56413

Alfa AF: 0.00840 Hom.: 348

Mitomap

Disease(s): Encephalopathy-/-gout

Status: Reported-[LB]

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	1	MELAS syndrome (2)
-	-	1	Mitochondrial disease (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	11
Hmtvar	Pathogenic	0.75
PhyloP100		0.28

Other links and lift over

dbSNP: rs200077222; hg19: chrM-5815;