Variant: NC_012920.1:m.7471dup

CA214937

42226 (ClinVar)

Gene: MT-TS1

Condition: mitochondrial disease

Inheritance Mode: Mitochondrial inheritance

UUID: 70c69556-61de-4e88-8de9-ae8b0bcba308

HGVS expressions

NC_012920.1:m.7471dup
J01415.2:m.7471dup

Pathogenic

The Expert Panel has overridden the computationally generated classification - "Likely Pathogenic"

• Met criteria codes: PS3_Supporting PP1_Moderate PS4

• Not Met criteria codes: PS2 PP3 PM6 PM2

Expert Panel

Mitochondrial Diseases VCEP

Criteria Specification Information

Evidence submitted by expert panel

Mitochondrial Diseases VCEP

The m.7471dup variant in MT-TS1 has been reported in >16 unrelated individuals with primary mitochondrial disease across several haplogroups. This variant is most commonly associated with sensorineural hearing loss however affected individuals can also have other features. Affected individuals have been reported with features including MELAS, cerebellar ataxia, myoclonus, epilepsy, white matter disease, intellectual disability, cerebellar atrophy, exercise intolerance, and hypotonia; and this variant has been seen in affected individuals in the homoplasmic and heteroplasmic states (PS4; PMIDs: 7581383, 9708714, 9832034, 9778262, 9778273, 10094190, 15482956, 11378827, 15292920, 15482956, 11378827, 15292920, 1533431, 16368237, 17637808, 15833431, 16368237). This variant segregated with disease in multiple affected members in multiple families and several healthy family members had lower to undetectable levels of the variant (PP1_moderate, PMIDs: 7581383, 9708714). Cybrid studies supported the functional impact of this variant (PS3_supporting; PMID: 10545608). There are no de novo occurrences to our knowledge. There are no in silico predictors for this type of variant in mitochondrial DNA. In summary, this variant meets criteria to be classified as likely pathogenic however this Expert Panel elected to modify the classification to pathogenic given the overwhelming evidence of pathogenicity. Furthermore, the mitochondrial DNA variant specifications are known to not be optimized for pathogenic variants that tend to be homoplasmic in nature, have reduced penetrance, and/or variants that are insertions. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on November 14, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied(PMID: 32906214): PS4, PP1_moderate, PS3_supporting.

Met criteria codes

• PS3_Supporting: Cybrid studies supported the functional impact of this variant (PS3_supporting; PMIDs: 10545608).
• PP1_Moderate: This variant segregated with disease in multiple affected members in multiple families and several healthy family members had lower to undetectable levels of the variant (PP1_moderate, PMIDs: 7581383, 9708714).
• PS4: The m.7471dup variant in MT-TS1 has been reported in >16 unrelated individuals with primary mitochondrial disease and across several haplogroups. This variant is most commonly associated with sensorineural hearing loss however affected individuals can also have other features. Affected individuals have been reported with features including MELAS, cerebellar ataxia, myoclonus, epilepsy, white matter disease, ID, cerebellar atrophy, exercise intolerance, hypotonia; and this variant has been seen in affected individuals in the homoplasmic and heteroplasmic states (PS4; PMIDs: 7581383, 9708714, 9832034, 9778262, 9778273, 10094190, 15482956, 11378827, 15292920, 15482956, 11378827, 15292920, 1533431, 16368237, 17637808, 15833431, 16368237).

Not Met criteria codes

• PS2: There are no de novo occurrence to our knowledge.
• PP3: There are no in silico predictors for this type of variant in mitochondrial DNA.
• PM6: There are no de novo occurrence to our knowledge.
• PM2: There are several occurrences in population databases, however some of these are from reported affected individuals. Heteroplasmic 26/56307 = 0.046%.

Approved on: 2022-11-14

Published on: 2023-01-05