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]
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  • There was no gene found in the curated document received from the VCI/VCEP
  • Gene listed was thus derived from ClinVar and/or CAR
  • See Evidence submitted by expert panel for details.

Variant: NC_012920.1:m.8851T>C

CA120598

9645 (ClinVar)

Gene: MT-ATP6
Condition: mitochondrial disease
Inheritance Mode: Mitochondrial inheritance
Link to MONDO
UUID: 40d4031b-7f71-46c7-b0ec-dcbc5f538b7e

HGVS expressions

NC_012920.1:m.8851T>C
J01415.2:m.8851T>C
ENST00000361899.2:n.325T>C

Uncertain Significance

Met criteria codes 4
PS4_Supporting PS3_Moderate PP1 PP3
Not Met criteria codes 5
PM4 PM5 PM2 BP4 PS1

Evidence Links 1

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Mitochondrial Diseases VCEP
The m.8851T>C (p.W109R) variant in MT-ATP6 has been reported in 4 individuals with features of primary mitochondrial disease from 3 families. Affected individuals had variable ages of onset (first months of life to 3 years old, one with onset in early 20s, one with onset in 50s). Several affected individuals had a period of normal development followed by delay and regression. Progressive neuromuscular involvement in later onset forms has also been seen. Features include developmental delay, microcephaly, choreoathetotic movements, ataxia, axonal neuropathy, progressive cognitive impairment, retinal dystrophy, hearing loss, and increase of subsarcolemmal mitochondria in muscle. Brain MRI showed bilateral basal ganglia lesions, Leigh syndrome, and cerebellar atrophy; and lab abnormalities included elevated blood and CSF lactate, and elevated ammonia with febrile viral infection. Heteroplasmy levels were generally variable, >68% in multiple tissues; one healthy mother had 85% heteroplasmy; and one healthy sib had 50-60% heteroplasmy (PS4_supporting; PMIDs: 8554662, 23206802, 33704825). There are no reports of de novo occurrence of this variant. 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; PMIDs: 8554662, 23206802). There are several occurrences of this variant in healthy population databases. Several studies in yeast (PMID: 31181185) support the functional impact of this variant and showed independent deleterious effects of the variant (PS3_moderate). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.69 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). 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/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on February 28, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS3_moderate, PS4_supporting, PP1, PP3.
Met criteria codes
PS4_Supporting
The m.8851T>C (p.W109R) variant in MT-ATP6 has been reported in 4 individuals with features of primary mitochondrial disease from 3 families. Affected individuals had variable ages of onset (first months of life to 3 years old, one with onset in early 20s, one with onset in 50s). Several affected individuals had a period of normal development followed by delay and regression. Progressive neuromuscular involvement in later onset forms has also been seen. Features include developmental delay, microcephaly, choreoathetotic movements, ataxia, axonal neuropathy, progressive cognitive impairment, retinal dystrophy, hearing loss, and increase of subsarcolemmal mitochondria in muscle. Brain MRI showed bilateral basal ganglia lesions, Leigh syndrome, and cerebellar atrophy; and lab abnormalities included elevated blood and CSF lactate, and elevated ammonia with febrile viral infection. Heteroplasmy levels were generally variable, >68% in multiple tissues; one healthy mother had 85% heteroplasmy; and one healthy sib had 50-60% heteroplasmy (PS4_supporting; PMIDs: 8554662, 23206802, 33704825).
PS3_Moderate
Several studies in yeast (PMID: 31181185) support the functional impact of this variant and showed independent deleterious effects of the variant (PS3_moderate). (Yeast models showing showing slow growth on non-fermentable carbon sources, more pronounced at 36C than 28C; and reduced ATP production, also most pronounced at 36C than 28C; reduced ATPase activity; subsequent study showing mechanism of deficits.)
Yeast model showing slow growth on non-fermentable carbon sources, more pronounced at 36C than 28C; and reduced ATP production, also most pronounced at 36C than 28C; reduced ATPase activity PubMed:31181185
PP1
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; PMIDs: 8554662, 23206802).
PP3
The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.69 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3).
Not Met criteria codes
PM4
This is a missense variant.
PM5
No other variants in this position.
PM2
There is are multiple occurrences in population databases. GenBank: 3 (1 individual from haplogroup H1c, reported in PMID: 20457583 - Malyarchuck et al., 2010 that reported sequences from individuals from Kazan Tatar and Mishar population in Russia who live in the territory of the middle Volga River basin; 1 individual from haplogroup M54, reported in PMID: 24002810 - Kang et al., 2013 that reported sequences from individuals from the Sherpa population who live in the south mountainside of the Himalayas; and 1 individual from haplogroup H3, reported in PMID: 28177087 - Olivieri et al., 2017 that reported sequences from individuals from Sardinian populations) gnomAD: 2 (1 homoplasmic occurrence in individual of Finnish descent; 1 homoplasmic occurrence in individual of African American descent; ages not specified; haplogroups were J and U however not specified which individual was in which haplogroup). Helix: 14 (10 homoplasmic occurrences in individuals from haplogroups A (3), U (3), H (2), J (1), and T (1); 4 heteroplasmic occurrences in individuals from haplogroups H (2), B (1), U (1)).
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No other variants in this position.
Approved on: 2022-03-24
Published on: 2022-03-24
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