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-CYB):m.15848A>G

CA16603354

377369 (ClinVar)

Gene: N/A

Condition: mitochondrial disease

Inheritance Mode: Mitochondrial inheritance

Link to MONDO

UUID: d9e390ba-9d56-4930-9079-efa6d0cebbab

HGVS expressions

NC_012920.1:m.15848A>G

J01415.2:m.15848A>G

ENST00000361789.2:n.1102A>G

Uncertain Significance

BP4

PS2 PS3 PS4 PP1 PM6 PM2 BA1 BS1

Evidence Links 0

Expert Panel

Mitochondrial Diseases VCEP

Criteria Specification Information

Criteria Specification: ClinGen Mitochondrial Disease Nuclear and Mitochondrial Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1_mtDNA

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Mitochondrial Diseases VCEP

The m.15848A>G (p.T368A) variant in MT-CYB was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel on July 10, 2023. There are no individuals or families with primary mitochondrial disease with this variant reported in the medical literature to our knowledge. This variant is present at varying frequencies in population databases. The frequency in the MITOMAP GenBank sequences in 38/59,389 (0.064%) spread over 13 top level (single letter) haplogroups with European, Asian, and African ancestry. The frequency of homoplasmic occurrences of this variant in the Helix dataset in 98/195,983 (0.050%), in addition to 10 heteroplasmic occurrences, spread over 15 top level haplogroups with European, Asian, and African ancestry. The frequency of homoplasmic occurrences in gnomAD v3.1.2 is 217/56,429 (0.385%) in addition to two heteroplasmic occurrences, spread over 13 top level haplogroups with European, Asian, and African ancestry. The overall frequency is notably higher in this database than in MITOMAP and Helix, with 185 of the gnomAD sequences categorized as Latin American and all in top level haplogroup A. Therefore, the frequency of this variant meets neither criteria for pathogenicity (<0.002%) nor benign status (>0.5%). The computational predictor APOGEE gives scores of 0.33 (“neutral”) in APOGEE1 and 0.0087 (“benign”) in APOGEE2 (Min=0, Max=1), predicting no impact on gene function (BP4). There are no cybrids, single fiber studies, or other functional assays reported for this variant to date. 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 ClinGen Mitochondrial Disease Variant Curation Expert Panel on July 10, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied: BP4.

BP4

This variant has raw scores in both APOGEE1 (0.33) and APOGEE2 (0.0087) of <0.5, which meets the criteria for a neutral or benign impact.

PS2

There are no individuals or families with primary mitochondrial disease with this variant reported in the medical literature to our knowledge.

PS3

There are no cybrids, single fiber studies, or other functional assays reported for this variant to date.

PS4

We found no published cases in our review of the literature. There are two reports in ClinVar: one submittal for an individual reportedly with Leigh Disease and another submittal with no clinical condition provided. We do not count undocumented ClinVar reports for curation.

PP1

There are no individuals or families with primary mitochondrial disease with this variant reported in the medical literature to our knowledge.

PM6

There are no individuals or families with primary mitochondrial disease with this variant reported in the medical literature to our knowledge.

PM2

This variant is present at varying frequencies in population databases. The frequency in the MITOMAP GenBank sequences in 38/59,389 (0.064%) spread over 13 top level (single letter) haplogroups with European, Asian, and African ancestry. The frequency of homoplasmic occurrences of this variant in the Helix dataset in 98/195,983 (0.050%), in addition to 10 heteroplasmic occurrences, spread over 15 top level haplogroups with European, Asian, and African ancestry. The frequency of homoplasmic occurrences in gnomAD v3.1.2 is 217/56,429 (0.385%) in addition to two heteroplasmic occurrences, spread over 13 top level haplogroups with European, Asian, and African ancestry. The overall frequency is notably higher in this database than in MITOMAP and Helix, with 185 of the gnomAD sequences categorized as Latin American and all in top level haplogroup A. Therefore, the frequency of this variant meets neither criteria for pathogenicity (<0.002%) nor benign status (>0.5%).

BA1

BS1

BS1 requires a database frequency of >0.5% for Strong evidential line of support. This variant was found at the following frequencies: Mitomap 38/59,389 FL Seq (0.064%); gnomAD 217/56,429 (0.385%): Helix 98/195,983 seq (0.050%). Additionally, in gnomAD the 219 cases (217 homoplasmic, 2 heteroplasmic) were spread globally over 12 different haplogroups of European, Asian, and African ancestry. Similarly, the 108 reports in Helix (98 homoplasmic. 10 heteroplasmic) were spread over 14 different haplogroups of European, Asian, and African ancestry. Of special interest is that in gnomAD, 185 of the 217 homoplasmic reports were in haplogroup A, representing 6.9% of their haplogroup A sequences.

Approved on: 2023-07-10

Published on: 2023-08-03

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