M-1624-C-T

Variant names:

• chrM-1624-C-T
• rs199476144
• unassigned_transcript_4786:c.23C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PS4_Moderate PP3 PS3_Moderate PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.1624C>T variant in MT-TV has been reported in two families with primary mitochondrial disease (PMIDs: 11799391, 23063709). The proband in the first family reported was a woman with migraines, muscle weakness, reduced COX activity on histochemistry in skeletal muscle, and reduced activities of complexes I and IV in skeletal muscle. The variant was present at homoplasmy in her blood and muscle sample. She had a son with Leigh syndrome with the variant present at homoplasmy in buccal sample. She had six other children who died in the first days of life due to lactic acidosis, including one child who also had severe cardiac failure and hypertrophic cardiomyopathy who was found to have the variant present at homoplasmy in blood, muscle, and cardiac tissue. She also had three siblings who died in early infancy (PMID:11799391). The proband in the second family reported was a man with adult-onset Leigh syndrome. He presented at age 25 years with transient mild consciousness disturbance and agitation. By 29 years he had left ventricular hypertrophy, constricted visual fields, ataxic gait, slurred speech, and poor coordination. By his mid-30s, he has personality changes and cognitive decline. He had elevated blood and cerebrospinal fluid lactate levels. Brain imaging at ages 25 years and 35 years revealed mild frontal lobe atrophy and low and high signal intensity spots on T1- and T2-weighted images, respectively, in the right caudate head and bilateral putamen. The variant was present in muscle (89% at age 29 years, 60% at age 36 years) and blood (48% at 29 years, 34% at age 36 years). His mother had onset of stroke-like episodes in her mid-30s in addition to psychiatric involvement. She was noted to have left-sided paresis in her 40s. The variant was present in her blood at 17% (PMID:23063709). Additionally, an Expert Panel member knew of an additional two cases (one baby, one adult) who were very ill and had the variant present at homoplasmy (PS4_moderate). There are no de novo occurrences of this variant reported to our knowledge. This variant is absent in MITOMAP. There are no homoplasmic occurrences in gnomAD v3.1.2 or the Helix dataset, however there is one heteroplasmic occurrence in gnomAD and two heteroplasmic occurrences in Helix. Although there are several heteroplasmic occurrences, the frequency is still low (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic (68.7 percentile) and HmtVAR predicts it to be pathogenic score of 0.45 (PP3). Strong cybrid studies and analysis in patient myoblasts and fibroblasts support the functional impact of this variant (PS3_moderate; PMID:18400783). 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 September 24, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PS4_moderate, PS3_moderate, PM2_supporting, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120537/MONDO:0044970/015

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 0)
• Consequence: TRNV unassigned_transcript_4786 missense
• Scores: Mitotip Uncertain 15
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4 O:1 Leigh-Syndrome
• Conservation: PhyloP100: 5.78
• Publications: 2 publications found

Genes affected

TRNV (HGNC:7500): (mitochondrially encoded tRNA valine)

MT-RNR2 (HGNC:7471): (mitochondrially encoded 16S RNA) Enables G protein-coupled receptor binding activity; protein self-association; and receptor antagonist activity. Involved in several processes, including leukocyte chemotaxis; negative regulation of cell death; and negative regulation of neuroinflammatory response. Located in several cellular components, including mitochondrion; perinuclear region of cytoplasm; and sperm midpiece. [provided by Alliance of Genome Resources, Apr 2022]

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.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: 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: ENST00000387342.1. 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-TV	ENST00000387342.1	TSL:6	n.23C>T		non_coding_transcript_exon	Exon 1 of 1
	MT-RNR2	ENST00000387347.2	TSL:6	n.-47C>T		upstream_gene	N/A
	MT-RNR1	ENST00000389680.2	TSL:6	n.*23C>T		downstream_gene	N/A

Frequencies

Mitomap GenBank AF: 0.0 AC: 0

Gnomad homoplasmic AF: 0.0 AC: 0 AN: 56433

Gnomad heteroplasmic AF: 0.000018 AC: 1 AN: 56433

Mitomap

Disease(s): Leigh-Syndrome

Status: Reported

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	MELAS syndrome (2)
1	-	-	Leigh syndrome, mitochondrial (1)
1	-	-	Mitochondrial disease (1)
-	-	-	Leigh syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	15
Hmtvar	Pathogenic	0.45
PhyloP100		5.8

Other links and lift over

dbSNP: rs199476144; hg19: chrM-1626;