Variant: m.14568C>T

CA344825

65515 (ClinVar)

Gene: N/A

Condition: mitochondrial disease

Inheritance Mode: Mitochondrial inheritance

UUID: 6fa819a8-103c-4395-8c9c-6bb33965995b

Approved on: 2022-06-30

Published on: 2022-06-30

HGVS expressions

NC_012920.1:m.14568C>T
J01415.2:m.14568C>T
ENST00000361681.2:c.106G>A

Likely Pathogenic

• Met criteria codes: PM2_Supporting PP1_Moderate PS4_Moderate PP3

• Not Met criteria codes: PM6 PS2 PS3

Expert Panel

Mitochondrial Diseases VCEP

Criteria Specification Information

Evidence submitted by expert panel

Mitochondrial Diseases VCEP

The m.14568C>T (p.G36S) variant in MT-ND6 has been reported in eight individuals from seven families, all of whom had LHON (PS4_moderate; PMIDs: 10447650, 19319978, 12324878, 22879922, 9177303). There are no reports of de novo occurrences to our knowledge. This variant segregated with disease in one family with LHON (affected individuals: proband and brother with heteroplasmy levels ranging from 60-90%; unaffected individuals: mother and maternal aunt with lower heteroplasmy levels; PP1_moderate; PMID: 22879922). There are several occurrences in population databases, however some of these are from reported affected individuals. Although there are several occurrences, the frequency is still low (PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.9 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). There are no cybrid studies, single fiber studies, or other functional assays reported for 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 Mitochondrial Disease Variant Curation Expert Panel on April 11, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PP1_moderate, PM2_supporting, PP3.

Met criteria codes

• PM2_Supporting: There are several occurrences in population databases, however some of these are from reported affected individuals. Although there are several occurrences, the frequency is still low (PM2_supporting). After removal of cases in the literature it is seen at a low prevalence: gnomAD variant is seen at 0.002% (1/56434), Helix 0.001% (2)
• PP1_Moderate: This variant segregated with disease in one family with LHON (affected individuals: proband and brother with heteroplasmy levels ranging from 60-90%; unaffected individuals: mother and maternal aunt with lower heteroplasmy levels; PP1_moderate; PMID: 22879922).
• PS4_Moderate: The m.14568C>T (p.G36S) variant in MT-ND6 has been reported in eight individuals from seven families, all of whom had LHON (PS4_moderate; PMIDs: 10447650, 19319978, 12324878, 22879922, 9177303).
• PP3: The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.9 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3).

Not Met criteria codes

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