chrM-7510-T-C

Variant names:

• chrM-7510-T-C
• rs199474820
• unassigned_transcript_4800:c.5A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PS4_Moderate PP1_Moderate PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.7510T>C variant in MT-TS1 has been reported in at least nine individuals across six different families with primary mitochondrial disease (PS4_moderate; PMIDs: 29299381, 18028453, 23430555, 15292920, 10978361, 12471220). The most common feature in affected individuals was sensorineural hearing loss. Age of onset ranged from 2-70 years old, and heteroplasmy levels in affected individuals ranged from 90% to >99%. Of note, some unaffected family members had the variant present at homoplasmy, as well (PMID:12471220). Additional clinical features were seen in at least two families. One family reported in the medical literature also had migraines, ataxia, short stature, epilepsy, cognitive impairment, tremor, and restless leg syndrome (PMID:29299381). The second family was known to some members of this expert panel, and the expert panel agreed to include this case. This variant segregated with disease manifestations in two families with hearing loss as all affected individuals had the variant present at heteroplasmy levels ranging from 90% to >99% (PP1_moderate; PMIDs: 29299381, 10978361). There are no de novo occurrences of this variant to our knowledge. The computational predictor MitoTIP suggests this variant is pathogenic (68.6 percentile) and HmtVAR predicts it to be pathogenic score of 0.6 (PP3). There is one occurrence in the GenBank population database, and the variant is absent in the Helix dataset and gnomAD v.3.1.2. Although there is one occurrence, the frequency is still low (PM2_supporting). There are no cybrids, single fiber studies, or other functional assays reported on this variant. 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 13, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PS4_moderate, PP1_moderate, PM2_supporting, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA340921/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: TRNS1 unassigned_transcript_4800 stop_gained
• Scores: Mitotip Uncertain 15
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 O:1 SNHL
• Conservation: PhyloP100: 1.24
• Publications: 2 publications found

Genes affected

TRNS1 (HGNC:7497): (mitochondrially encoded tRNA serine 1 (UCN))

MT-CO2 (HGNC:7421): (mitochondrially encoded cytochrome c oxidase II) Contributes to cytochrome-c oxidase activity. Predicted to be involved in mitochondrial electron transport, cytochrome c to oxygen and positive regulation of vasoconstriction. Located in mitochondrial inner membrane. Part of respiratory chain complex IV. Biomarker of Huntington's disease and stomach cancer. [provided by Alliance of Genome Resources, Apr 2022]

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]

TRND (HGNC:7478): (mitochondrially encoded tRNA aspartic acid)

TRND Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• 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: ENST00000387416.2. 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-TS1	ENST00000387416.2	TSL:6	n.5A>G		non_coding_transcript_exon	Exon 1 of 1
	MT-CO2	ENST00000361739.1	TSL:6	c.-76T>C		upstream_gene	N/A	ENSP00000354876.1	P00403
	MT-CO1	ENST00000361624.2	TSL:6	c.*65T>C		downstream_gene	N/A	ENSP00000354499.2	P00395

Frequencies

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

Alfa AF: 0.00 Hom.: 0

Mitomap

Disease(s): SNHL

Status: Cfrm-[LP]

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	Mitochondrial disease (1)
1	-	-	Mitochondrial non-syndromic sensorineural hearing loss (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	15
Hmtvar	Pathogenic	0.60
PhyloP100		1.2
Mutation Taster		=100/0	disease causing (ClinVar)

Other links and lift over

dbSNP: rs199474820; hg19: chrM-7511;