rs118203888

Positions:

• chrM-12258-C-A
• chrM-12258-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PP3 PS4_Supporting PM2_Supporting PS3_Supporting PP1_Moderate

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: MT-TS2 ENST00000387449.1 non_coding_transcript_exon
• 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

Genes affected

MT-TS2 (HGNC:7498): (mitochondrially encoded tRNA serine 2 (AGU/C))

TRNS2 (HGNC:):

MT-TL2 (HGNC:7491): (mitochondrially encoded tRNA leucine 2 (CUN))

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRNS2	TRNS2.1	n.52C>A		non_coding_transcript_exon_variant	1/1
TRNL2	TRNL2.1			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MT-TS2	ENST00000387449.1	n.52C>A		non_coding_transcript_exon_variant	1/1
MT-TL2	ENST00000387456.1			upstream_gene_variant

Frequencies

GnomAD4 exome Cov.: 0

We have no GnomAD4 genomes data on this position. Probably position not covered by the project.

Mitomap

DMDF-/-RP+SNHL,Unspecified-patient-from-clinical-lab

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial disease Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen

Mar 28, 2023

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. -

Retinitis pigmentosa-deafness syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 1999

- -

Cerebellar ataxia, cataract, and diabetes mellitus Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 1999

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Pathogenic	20
Hmtvar	Pathogenic	0.40

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs118203888; hg19: chrM-12259;