rs118203888

Variant names:

• chrM-12258-C-A
• rs118203888
• unassigned_transcript_4813:c.52C>A

Your query was ambiguous. Multiple possible variants found:

• chrM-12258-C-A
• chrM-12258-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PS3_Supporting PP1_Moderate PP3 PS4_Supporting PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.12258C>A variant in MT-TS2 gene has been reported in two unrelated individuals with primary mitochondrial disease (PS4_supporting). Family members of both probands were also affected. The age of onset was in adulthood and ranged from the 20s to 60s. Features seen in affected individuals include diabetes, cataracts, retinitis pigmentosa, hearing loss, and cerebellar ataxia (PMIDs: 9792552, 10090882). This variant segregated with disease in multiple affected members in both families and several healthy family members had lower to undetectable levels of the variant (PP1_moderate; PMIDs: 10090882, 9792552). There are no reported de novo occurrences of this variant to our knowledge. There is one occurrence in population databases (one occurrence in Mitomap GenBank sequences, absent in gnomAD v3.1.2 and Helix dataset). Although there is one occurrence, the frequency is still low (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic (95.3 percentile) and HmtVAR predicts it to be pathogenic with a score of 0.4 (PP3). Single fiber studies support the functional impact of this variant (PS3_supporting) as the level of variant in COX-positive fibers ranged from 23-71%, while in COX-negative fibers was present at >85% heteroplasmy (PMID:9792552). 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 March 28, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PS4_supporting, PP1_moderate, PM2_supporting, PP3, PS3_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120544/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: TRNS2 unassigned_transcript_4813 missense
• Scores: Mitotip Pathogenic 20
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3 DMDF-/-RP+SNHL,Unspecified-patient-from-clinical-lab
• Conservation: PhyloP100: 1.09
• Publications: 1 publications found

Genes affected

TRNS2 (HGNC:7498): (mitochondrially encoded tRNA serine 2 (AGU/C))

MT-ND5 (HGNC:7461): (mitochondrially encoded NADH dehydrogenase 5) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly. Part of mitochondrial respiratory chain complex I. Implicated in Leber hereditary optic neuropathy; Leigh disease; and MELAS syndrome. [provided by Alliance of Genome Resources, Apr 2022]

MT-ND4 (HGNC:7459): (mitochondrially encoded NADH dehydrogenase 4) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly. Part of mitochondrial respiratory chain complex I. Implicated in Leber hereditary optic neuropathy; Parkinson's disease; macular degeneration; and schizophrenia. Biomarker of Alzheimer's disease. [provided by Alliance of Genome Resources, Apr 2022]

TRNL2 (HGNC:7491): (mitochondrially encoded tRNA leucine 2 (CUN))

TRNH (HGNC:7487): (mitochondrially encoded tRNA histidine)

TRNH Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• MERRF syndrome

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet

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.
• 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: ENST00000387449.1. 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-TS2	ENST00000387449.1	TSL:6	n.52C>A		non_coding_transcript_exon	Exon 1 of 1
	MT-ND5	ENST00000361567.2	TSL:6	c.-79C>A		upstream_gene	N/A	ENSP00000354813.2	P03915
	MT-ND4	ENST00000361381.2	TSL:6	c.*121C>A		downstream_gene	N/A	ENSP00000354961.2	P03905

Frequencies

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

Alfa AF: 0.00 Hom.: 0

Mitomap

Disease(s): DMDF-/-RP+SNHL,Unspecified-patient-from-clinical-lab

Status: Cfrm-[LP],Reported

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	Cerebellar ataxia, cataract, and diabetes mellitus (1)
1	-	-	Mitochondrial disease (1)
1	-	-	Retinitis pigmentosa-deafness syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Mitotip	Pathogenic	20
Hmtvar	Pathogenic	0.40
PhyloP100		1.1

Other links and lift over

dbSNP: rs118203888; hg19: chrM-12259;