Criteria Specification Registry

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Criteria Specification

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

Description : This document contains one of the two sets of ACMG/AMP specifications from the ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel

Version : 1.0.0

PDF

Mitochondrial Diseases VCEP

Released

4/30/2020

00:00:00

Rules for Mitochondrial Genes

Criteria & Strength Specifications
PVS1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Caveats: • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7). • Use caution interpreting LOF variants at the extreme 3’ end of a gene. • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact. • Use caution in the presence of multiple transcripts. Stand Alone Very Strong Large heteroplasmic mtDNA deletions, where at least one gene is completely deleted Strong Assessment of small deletions, nonsense, and frameshift variants in protein-coding genes should follow established guidelines (Abou Tayoun et al., 2018) Moderate Assessment of small deletions, nonsense, and frameshift variants in protein-coding genes should follow established guidelines (Abou Tayoun et al., 2018) Supporting Assessment of small deletions, nonsense, and frameshift variants in protein-coding genes should follow established guidelines (Abou Tayoun et al., 2018) Not Applicable Comments: Nonsense mediated decay is not known to occur for mtDNA, however ClinGen SVI PVS1 guidelines (Abou Tayoun et al., 2018) will be utilized when applicable (see figure).
PS1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level. Stand Alone Very Strong Strong Applied per original ACMG/AMP guidelines Moderate Supporting Not Applicable
PS2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity. Stand Alone Very Strong De novo (maternity confirmed or identical full mtDNA sequence) in a patient with the disease and no family history; with weighting per ClinGen SVI guidance Strong De novo (maternity confirmed or identical full mtDNA sequence) in a patient with the disease and no family history; with weighting per ClinGen SVI guidance Moderate De novo (maternity confirmed or identical full mtDNA sequence) in a patient with the disease and no family history; with weighting per ClinGen SVI guidance Supporting De novo (maternity confirmed or identical full mtDNA sequence) in a patient with the disease and no family history; with weighting per ClinGen SVI guidance Not Applicable Comments: Older sequencing techniques such as Sanger sequencing cannot reliably detect heteroplasmy levels below 30-50%. Current NGS techniques can typically detect heteroplasmy levels as low as 1.5%. It is recommended to test several tissues in the mother to fully assess for the presence and level of the mtDNA variant in question. Utilize ClinGen SVI recommendation for applying these criteria (https://clinicalgenome.org/site/assets/files/3461/ svi_proposal_for_de_novo_criteria_v1_0.pdf), the mitochondrial genome would best fit with Table 1 “phenotypic consistency” category of “phenotype consistent with gene but not highly specific.”
PS3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established. Stand Alone Very Strong Strong Moderate Supporting Functional validation is present in cybrid studies or single fiber analysis Not Applicable Comments: The following criteria should be met to apply: * a biochemical deficiency must be observed in patient cell line with mtDNA variant in question. * whether the biochemical deficiency is transferred to mutant cybrids (in the case of enzymatic deficiency, <20% activity of control or a decrease in activity that is >2 standard deviations from control mean. * whether cybrid cells carry high mutant load (minimal 60%). * if studies have been reproduced and are consistent.
PS4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance. Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence. Stand Alone Very Strong Strong Variant present in ≥16 unrelated probands Moderate Variant present in ≥4 unrelated probands Supporting Variant present in 2 unrelated probands in different top-level haplogroups Not Applicable Comments: Individuals are defined as affected if they: * meet diagnostic criteria for one of the classic mitochondrial disease clinical syndromes (MELAS, MERRF, MIDD, NARP, Pearson, KSS, CPEO, CPEO plus, Leigh, Alpers, LHON, primary lactic acidosis). OR * have 1 “red flag” feature with 2 or more nonspecific features (see tables in Haas et al., 2007) OR * have 3 or more nonspecific features with lab abnormalities (see table in Haas et al., 2008).
PM1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. Stand Alone Very Strong Strong Moderate Supporting Not Applicable
PM2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. Caveat: Population data for indels may be poorly called by next generation sequencing. Stand Alone Very Strong Strong Moderate Supporting Frequency <0.00002 (0.002%, 1/50,000) from controls Not Applicable
PM3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary For recessive disorders, detected in trans with a pathogenic variant Note: This requires testing of parents (or offspring) to determine phase. Stand Alone Very Strong Strong Moderate Supporting Not Applicable Comments: mtDNA variants are maternally inherited and not inherited in an autosomal recessive manner.
PM4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. Stand Alone Very Strong Strong Moderate Applied per original ACMG/AMP guidelines Supporting Not Applicable
PM5 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level. Stand Alone Very Strong Strong Moderate Applied per original ACMG/AMP guidelines (protein-coding genes) Supporting Same nucleotide position as previously established pathogenic variant in a rRNA/tRNA Not Applicable
PM6 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Assumed de novo, but without confirmation of paternity and maternity. Stand Alone Very Strong Assumed de novo, but without confirmation of maternity (maternal testing done by targeted variant analysis and/or targeted gene sequencing) Strong Assumed de novo, but without confirmation of maternity (maternal testing done by targeted variant analysis and/or targeted gene sequencing) Moderate Assumed de novo, but without confirmation of maternity (maternal testing done by targeted variant analysis and/or targeted gene sequencing) Supporting Assumed de novo, but without confirmation of maternity (maternal testing done by targeted variant analysis and/or targeted gene sequencing) Not Applicable
PP1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. Note: May be used as stronger evidence with increasing segregation data. Stand Alone Very Strong Strong Moderate Co-segregation with disease in 5+ maternal family members and level of heteroplasmy segregating with disease manifestations Supporting Co-segregation with disease in 2-4 maternal family members and level of heteroplasmy segregating with disease manifestations Not Applicable Comments: Variant must not only segregate in maternal family members, but the level of heteroplasmy must also segregate with disease manifestations, where those individuals with more mild symptoms or appearing to be healthy have lower to undetectable levels of the variant and those more severely affected individuals and/or tissues have higher levels of the variant. This criterion cannot be applied when a variant is present at homoplasmy in multiple family members.
PP2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. Stand Alone Very Strong Strong Moderate Supporting Not Applicable Comments: mtDNA exhibits lack of recombination and a relatively high mutation rate (due to lack of histones or other protective structures) that allows for mtDNA variants to accumulate over time.
PP3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant. Stand Alone Very Strong Strong Moderate Supporting Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, etc) Not Applicable
PP4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology. Stand Alone Very Strong Strong Moderate Supporting Decreased ETC enzyme activity (<20%) performed in a CLIA-approved (or equivalently-certified) laboratory in muscle, liver, and/or fibroblasts (for fibroblasts, must be seen in multiple unrelated probands and/or assayed in different individuals). Not Applicable Comments: Other causes of ETC enzyme deficiency must be excluded, to the best of current ability, by comprehensive mtDNA and nDNA sequencing. Nuclear DNA genes including ETC complex subunits, assembly factors, and translation components should be thoroughly evaluated with no pathogenic or likely pathogenic variants (present in trans if autosomal recessive inheritance) that could be causative detected. See Supplemental file for list of genes.
PP5
Original ACMG Summary Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation. Not Applicable This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. PubMed : 29543229
BA1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. Stand Alone Top-level haplogroup defining variants in individuals that are members of that same top-level haplogroup OR Allele frequency > 0.01 (1%) Very Strong Strong Moderate Supporting Not Applicable
BS1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Allele frequency is greater than expected for disorder. Stand Alone Very Strong Strong Allele frequency 0.005 - 0.0099 (0.5% - 0.99%) Moderate Supporting Not Applicable
BS2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. Stand Alone Very Strong Strong Observed at a higher heteroplasmy in a healthy adult individual, especially in healthy maternal family members, than in same tissue tested in an affected individual Moderate Supporting Observed at a higher heteroplasmy in a healthy adult individual, especially in healthy maternal family members, than in different tissue(s) tested in an affected individual Not Applicable
BS3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing. Stand Alone Very Strong Strong Moderate Supporting No evidence of functional effect in cybrid studies or single fiber analysis is present (no statistically significant difference from control; mean values of <2 SD from control mean, or 50% enzyme activity compared to controls). Not Applicable
BS4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Lack of segregation in affected members of a family. Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation. Stand Alone Very Strong Strong Lack of segregation in affected members of a family and/or segregation of disease in paternal family members Moderate Supporting Not Applicable
BP1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Missense variant in a gene for which primarily truncating variants are known to cause disease. Stand Alone Very Strong Strong Moderate Supporting Not Applicable Comments: Most variants in protein-coding mtDNA genes are not truncating, but rather missense variants. Even if truncating variants were more common, this would not preclude missense variants from also causing a loss of protein function.
BP2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern. Stand Alone Very Strong Strong Moderate Supporting Other mtDNA variant is observed in individual’s mtDNA that has previously been confirmed to be pathogenic Not Applicable
BP3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary In frame-deletions/insertions in a repetitive region without a known function. Stand Alone Very Strong Strong Moderate Supporting Not Applicable Comments: There are a few locations in the mtDNA genome where indels within a repetitive region are observed outside of two common locations: one is in the hypervariable region 1 (around position 16,189) and the other in hypervariable region 2 (around position 310). These indels are well-known benign findings.
BP4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant. Stand Alone Very Strong Strong Moderate Supporting Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, etc) Not Applicable
BP5 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Variant found in a case with an alternate molecular basis for disease. Stand Alone Very Strong Strong Moderate Supporting Mitochondrial DNA variant found in a case with a nuclear DNA-related disease Not Applicable
BP6
Original ACMG Summary Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation. Not Applicable This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. PubMed : 29543229
BP7 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. Stand Alone Very Strong Strong Moderate Supporting A synonymous (silent) variant. Not Applicable Comments: Mitochondrial genes do not undergo splicing. Conservation is included in predictor algorithms used in PP3 and BP4, so conservation will be incorporated in this criterion.