Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
Link to SEPIO compliant JSON-LD document
  • No ClinVar Id was directly found from the curated document
  • There was no gene found in the curated document received from the VCI/VCEP
  • Gene was also not found in ClinVar or the Allele Registry
  • See Evidence submitted by expert panel for details.

Variant: NC_012920.1:m.8936T>A

CA414799043

Gene: N/A
Condition: mitochondrial disease
Inheritance Mode: Mitochondrial inheritance
Link to MONDO
UUID: b279753c-4ebd-4f4f-945c-f9dbd39a3f05
Approved on: 2021-05-07
Published on: 2021-10-22

HGVS expressions

NC_012920.1:m.8936T>A
J01415.2:m.8936T>A
ENST00000361899.2:n.410T>A

Uncertain Significance

Met criteria codes 2
PP3 PM2_Supporting
Not Met criteria codes 11
PS1 PS3 PS4 BA1 PP1 PP4 PM5 PM6 BS2_Supporting BS3 BS1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Mitochondrial Diseases VCEP
The m.8936T>A (p.L137H) variant in MT-ATP6 has been reported in one family (PMID: 29929013), in a proband with Leigh syndrome and his unaffected mother. Unaffected mother had lower variant heteroplasmy than the proband in blood (8.26% vs 10.92%) and saliva (5.71% vs 8.26%). Family haplogroup is M30d1. There are no reports of de novo occurrence of this variant. This variant is located at the same amino acid position as another variant in ClinVar (m.8936T>C, ClinVar ID: 693028), but that variant is classified as of uncertain significance so cannot be considered evidence for pathogenicity. There are no large families to consider for evidence of segregation. This variant is absent in population databases (PM2_supporting). In silico tools (APOGEE) predict this variant to be pathogenic (PP3). There are no cybrid or single fiber studies reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD U24 Mitochondrial Disease Variant Curation Expert Panel on March 22, 2021. Mitochondrial DNA-specific ACMG/AMP criteria applied: PM2_supporting, PP3).
Met criteria codes
PP3
APOGEE score >0.50 (0.52/P)
PM2_Supporting
Homoplasmic AF: 0% (0/51836) GenBank sequences) in Mitomap; 0% (0/56368) in gnomAD.v3.1; 0% (0/195983) in Helix
Not Met criteria codes
PS1
Searched for confirmed pathogenic variants in Mitomap, gnomAD, ClinVar, hmtvar, & MSeqDR for a non-synonymous change at this position and did not find. However, ClinVar does have a VUS at this same position in a LS patient, m.8936T>C p.Leu137Pro
PS3
No studies published to date.
PS4
Only a single case reported to date (Angural et al PMID: 29929013) with novel variant in patient and his unaffected mother. Two other siblings died from causes unrelated to mitochondrial disease. The unaffected mother has a lower variant heteroplasmy then the patient in blood (8.26% vs 10.92%) and saliva (5.71% vs 8.26%). The patient was diagnosed with Leigh syndrome with additional atypical symptoms of Basal Ganglia Calcifications and late survival age. Family haplogroup is M30d1.
BA1
0% (0/51673 GenBank sequences) in Mitomap
PP1
Only a single case reported to date (Angural et al PMID: 29929013) with novel variant in patient and his unaffected mother. Two other siblings died from causes unrelated to mitochondrial disease. The unaffected mother has a lower variant heteroplasmy then the patient in blood (8.26% vs 10.92%) and saliva (5.71% vs 8.26%). The patient was diagnosed with Leigh syndrome with additional atypical symptoms of Basal Ganglia Calcifications and late survival age.
PP4
no ETC studies reported to date
PM5
ClinVar has an alternate allele/amino acid change at this position in a Leigh Syndrome patient listed as VUS [VCV000693028.1]. This alternate allele is m.8936T>C (p.Leu137Pro) vs the this m.8936T>A (p.Leu137His) allele. If the assessment of the alternate allele changes from a VUS to Pathogenic, then PM5 will be met for the current allele at the supporting level.
PM6
variant is maternally inherited in only case reported to date (Angural et al PMID: 29929013)
BS2_Supporting
The unaffected mother (Angural et al PMID: 29929013) also has the heteroplasmic variant but at slightly lower levels in two tissues: blood (8% mom vs 11% patient); saliva (6% mom vs 8% patient).
BS3
No studies published to date.
BS1
only single family with this variant described to date (Angural et al PMID: 29929013)
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