Evidence Repository - Clinical Genome Resources

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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Variant: NC_012920.1(MT-ATP6):m.8932C>T

CA10581280

235343 (ClinVar)

Gene: MT-ATP6

Condition: mitochondrial disease

Inheritance Mode: Mitochondrial inheritance

Link to MONDO

UUID: a07bb60a-eb8b-42fb-b578-0939e125baca

HGVS expressions

NC_012920.1:m.8932C>T

J01415.2:m.8932C>T

ENST00000361899.2:n.406C>T

Benign

BP4 BA1

PP3 PM2

Evidence Links 4

Expert Panel

Mitochondrial Diseases VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Mitochondrial Diseases VCEP

The m.8932C>T (p.P136S) variant in MT-ATP6 reaches benign stand-alone criteria (BA1) based on overall allele frequency [gnomAD.v3.1: Overall AF is 1.327% (759/56428); in top-level haplogroup L3, AF is 12.89% (731/5669) Mitomap: Overall AF in Mitomap is 0.399% (207/51863; in top-level haplogroup L3, AF is 9.73%. For the individuals in sub-group L3f, the frequency is 81% (205/253)]. Furthermore, this variant is reported in Phylotree as an L3f1b branch marker. There is one reported proband in the medical literature with this variant (PMID: 26993169), however when haplotyped by this curation team using the variants listed in the published report, the proband belonged to haplogroup L3f (haplogroup with which this variant is associated). In silico tools (APOGEE) predict this variant to be neutral (BP4). There are no cybrid or single fiber studies reported on this variant. In summary, this variant meets criteria to be classified as benign for primary mitochondrial disease inherited in a mitochondrial manner. However, if this variant is identified in an individual who is a member of a different haplogroup than described above, consider further evaluation of this variant. 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: BA1, BP4).

BP4

APOGEE consensus:rating is Neutral, ≤0.5. Species conservation is 66.7% (Mitomap)

BA1

Qualifies as stand-alone based on overall allele frequency in gnomAD (1.3%, homoplasmic occurrences) gnomAD.v3.1: Overall AF is 1.327% (759/56428); in top-level haplogroup L3, AF is 12.89% (731/5669) Mitomap: Overall AF in Mitomap is 0.399% (207/51863; in top-level haplogroup L3, AF is 9.73%. For the individuals in sub-group L3f, the frequency is 81% (205/253). This variant is reported in Phylotree as an L3f1b branch marker. Note of interest: a Tunisian patient with a mitochondrial neuromuscular disorder who carried this variant was haplotyped by the curator as L3f using variants listed in the published report [Felhi R et al 2016 PMID 26993169].

Branch marker in haplogroup L3f (L3f1b) PubMed:18853457

Seen in 1 stroke patient (haplogroup U). PubMed:11406419

Found in tumor sample #18 (no haplogroup information given). PubMed:15647368

One Tunisian mitochondrial neuromuscular disorder (haplotypes as L3f using patient variants reported in paper). The 8932T variant was reported in tandem with m.8527A>G transition at the junction MT-ATP6/MT-ATP8, another L3f marker. PubMed:26993169

PP3

APOGEE consensus rating is Neutral, ≤ 0.5

PM2

See notes for BA1

Approved on: 2021-05-07

Published on: 2021-10-22

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