Variant: m.7510T>C

CA340921

9565 (ClinVar)

Gene: MT-TS1

Condition: mitochondrial disease

Inheritance Mode: Mitochondrial inheritance

UUID: 12cdaa43-4011-4979-84ee-ad9fe7713461

HGVS expressions

NC_012920.1:m.7510T>C
J01415.2:m.7510T>C

Likely Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"

• Met criteria codes: PM2_Supporting PP1_Moderate PS4_Moderate PP3

• Not Met criteria codes: PS3 PS2 PM6

Expert Panel

Mitochondrial Diseases VCEP

Criteria Specification Information

Criteria Specification: ClinGen Mitochondrial Disease Nuclear and Mitochondrial Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1_mtDNA

Evidence submitted by expert panel

Mitochondrial Diseases VCEP

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.

Met criteria codes

• PM2_Supporting: 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).
• PP1_Moderate: 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).
• PS4_Moderate: 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.
• PP3: The computational predictor MitoTIP suggests this variant is pathogenic (68.6 percentile) and HmtVAR predicts it to be pathogenic score of 0.6 (PP3).

Not Met criteria codes

• PS3: There are no cybrids, single fiber studies, or other functional assays reported on this variant.
• PS2: There are no de novo occurrences of this variant to our knowledge.
• PM6: There are no de novo occurrences of this variant to our knowledge.

Approved on: 2023-03-13

Published on: 2023-03-17