chrM-5814-T-C
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_StrongBS2
Variant has been reported in ClinVar as Likely benign (★★★).
Frequency
Consequence
missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Benign. Variant got -12 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| TRNC | unassigned_transcript_4797 | c.13A>G | p.Ile5Val | missense_variant | Exon 1 of 1 | |||
| COX1 | unassigned_transcript_4799 | c.-90T>C | upstream_gene_variant | |||||
| TRNN | unassigned_transcript_4796 | c.-85A>G | upstream_gene_variant |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|
Frequencies
GnomAD4 exome Cov.: 0
Mitomap
ClinVar
Submissions by phenotype
MELAS syndrome Pathogenic:1Benign:1
- -
The NC_012920.1:m.5814T>C variant in MT-TC gene is interpreted to be a Benign variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes reported in the guidelines: BS1, BS2 -
not provided Uncertain:1
This variant (rs200077222) affects the MT-TC gene which encodes the mitochondrial tRNA for cysteine, and has been described in the literature as both a pathogenic and benign variant. The m.5814T>C variant has historically been associated with MELAS-like syndromes, having been found in a heteroplasmic state in a Portuguese patient with episodic vomiting, lactic acidosis, seizures, hemiparesis and white matter abnormalities identified in a brain MRI (Manfredi 1996). It was also identified (heteroplasmic) in an Italian proband with hearing impairment, unsteady gait, hyporeflexia, nystagmus, and lactic acidosis (Santorelli 1997). However, the m.5814T>C variant was also identified in mildly effected and unaffected maternal relatives of the proband described in Santorelli (1997), and identified in a homoplasmic state in a different proband whose only clinical presentation was exercise intolerance and who also had several unaffected maternal relatives who carried the variant in a homoplasmic state (Sternberg 2001). Additionally, the m.5814T>C variant is found at 99% allele frequency in the L2b haplogroup which is primarily carried by individuals of African and Dominican descent (MITOMAP; trees described in Herrnstadt 2002 and Kivisild 2006), and is therefore present in presumably healthy individuals. Based on the available evidence, the m.5814T>C variant is unlikely to be a primary MELAS variant; however, a contributory role of this variant to MELAS expression cannot be excluded. -
Mitochondrial disease Benign:1
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at