Criteria Specification Registry

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Criteria Specification

ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GCK Version 1.1.0

Description : ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version

Version : 1.1.0 Release Notes :

Updated language in PP4: “…patients tested because of neonatal diabetes, PP4 can be applied if there has been negative testing for monogenic causes for neonatal diabetes (ABCC8, KCNJ11, INS [if there is no consanguinity] EIF2AK3 [if there is consanguinity])” to “For patients tested because of neonatal diabetes, PP4 can be applied if there has been negative testing for major monogenic causes for neonatal diabetes. These include ABCC8, KCNJ11, and INS. In consanguineous cases, EIF2AK3 should be tested as well.”

Monogenic Diabetes VCEP

Released

3/23/2023

20:26:27

Rules for GCK

Gene: GCK (HGNC:4195) HGNC Name: glucokinase Transcripts: NM_000162.5 Disease: monogenic diabetes (MONDO:0015967) Mode of Inheritance: Autosomal dominant inheritance

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 Use GCK PVS1 decision tree created based on PVS1 decision tree from ClinGen SVI group¹ Variants generating PTCs 3’ of c.1198 (p.Asp400) of NM_000162.3, which includes the last 55 nucleotides of exon 9 and exon 10, are not expected to cause NMD². The α13 helix (p.444-456), located at the C-end of the protein, has a critical role in GCK conformational change upon glucose binding. Individuals with PTCs in exon 10 have a MODY phenotype. Therefore, a “very strong” level of evidence will be applied for PTCs in exon 10. “Exon skipping or “use of a cryptic splice site that preserves reading frame” and “Single to multi-exon deletion that preserves reading frame” single exon deletions deletion of exon 1 is in-frame but over 20 families with GCK-MODY phenotype and exon 1 deletion (some also have promoter deletions) --> PVS1 deletions of single exons 2,3,6 and 7 cause frameshift --> PVS1 deletions or skipping of exons 8 and 9 are in-frame and the proportion is >10 % (52 AA and 78 AA, respectively) --> PVS1 deletions or skipping of exons 4 and 5 are in-frame and the proportion is <10 % (40 AA and 32 AA, respectively). Exon 4 (p.122-161) and exon 5 (p.162-193) contain each a part of the active site that binds glucose /p.151-180³ according to Beck et al., Biochemistry 2013/ --> PVS1 deletion of exon 10 (47 AA) – There are a number of patients with a GCK-MODY phenotype with reported with missense, frameshift, PTC, splice acceptor, and stop loss variants in exon 10 --> PVS1 Apply PVS1_Supporting to initiation codon variants given MDEP has only reviewed one variant and classified as VUS (c.3G>A, PVS1_Supporting + PM2_Supporting; one case submitted, dx.53 and no other info provided to lab). The next methionine is at codon 8 and there are no variants classified as pathogenic 5' of p.Met8. Per recommendations from the SVI, when RNA analysis demonstrates abnormal splicing from non-canonical splice site variants, apply PS3 instead of PVS1. Modification Type: Gene-specific Strong Use GCK PVS1 decision tree. Per the SVI standard PVS1 decision tree, apply PVS1_Strong to duplications ≥ 1 exon in size, contained completely within gene, proven not in tandem, reading frame presumed disrupted, and NMD predicted to occur. Modification Type: Strength Moderate Supporting Use GCK PVS1 decision tree. Apply PVS1_Supporting to initiation codon variants given MDEP has only reviewed one variant and classified as VUS (c.3G>A, PVS1_Supporting + PM2_Supporting; one case submitted, dx.53 and no other info provided to lab). The next methionine is at codon 8 and there are no variants classified as pathogenic 5' of p.Met8. Per recommendations from the SVI, when RNA analysis demonstrates abnormal splicing from non-canonical splice site variants, apply PS3 instead of PVS1. Modification Type: Strength Instructions: Use GCK PVS1 decision tree. Not Applicable Comments: Per guidance from ClinGen/SVI, PM2_Supporting + PVS1 is sufficient evidence of a variant being likely pathogenic
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 No change Modification Type: None Moderate Supporting PS1 may be used at a supporting level for canonical and non-canonical splicing variants when a different variant at the same nucleotide has been previously classified as pathogenic and the variant being assessed is predicted by SpliceAI to have a similar (SpliceAI score within 10% of the original variant) or greater deleterious impact. Modification Type: Strength 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 Use SVI-recommended point-based system with specifications for “Phenotype Consistency” per instructions. . Modification Type: Gene-specific,Strength Strong Use SVI-recommended point-based system with specifications for “Phenotype Consistency” per instructions. Modification Type: Gene-specific,Strength Moderate Use SVI-recommended point-based system with specifications for “Phenotype Consistency” per instructions. Modification Type: Gene-specific,Strength Supporting Use SVI-recommended point-based system with specifications for “Phenotype Consistency” per instructions. Modification Type: Gene-specific,Strength Instructions: To obtain maximum points (“phenotype highly specific for gene”), patient must meet criteria for PP4. To obtain standard points (“phenotype consistent with gene but not highly specific”), the phenotype of the patient must include hyperglycemia or impaired fasting glucose, with no evidence of an autoimmune etiology of diabetes and/or absolute or near-absolute insulin deficiency. Exclusionary evidence of an autoimmune etiology of diabetes and/or absolute or near-absolute insulin deficiency includes the following: One or more positive diabetes autoantibodies (IA-2A, ZnT8A+, GAD) (Ref 15, 16, 17, 18). Very low or negative C-peptide, defined as either fasting or non-fasting random C-peptide (<200pmol/L or 0.6ng/mL) (Ref 13, 14) or urinary C-peptide/creatinine ratio <0.2 nmol/mmol (Ref 16, 17). We expect to see hyperglycemia at birth in an individual with GCK-MODY and therefore consider an individual unaffected if euglycemic in childhood or adulthood. Since individuals typically do not present with symptoms of diabetes, a statement that someone is “nondiabetic” is insufficient to consider a parent unaffected; fasting glucose must be tested and found to be within normal limits (<100 mg/dl = 5.5 mmol/L) or HbA1c <=5.5% (37 mmol/mol) since the GCK range was 5.6 - 7.6% (38 – 60 mmol/mol)(Ref 19). Presence of clinically significant diabetes complications in anyone with the variant is an exclusion. Not Applicable Comments: To obtain maximum points (“phenotype highly specific for gene”) patient must meet criteria for PP4 (result of ≥50% chance or higher of testing positive for MODY on the MODY Probability calculator (https://www.diabetesgenes.org/mody-probability-calculator/) AND have negative HNF4A testing). If patient does not meet PP4 but is noted to have diabetes, use points corresponding to “phenotype consistent with gene but not highly specific”. If patient shows evidence of an autoimmune etiology for their diabetes and/or absolute or near-absolute insulin deficiency (see above), do not apply PS2.
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 Applicable to non-canonical splice site variants that have RNA and in silico evidence of aberrant splicing. Modification Type: Gene-specific,Strength Moderate See list of approved functional studies and guidelines for interpretation of data. Modification Type: Gene-specific,Strength Supporting See list of approved functional studies and guidelines for interpretation of data (below). Modification Type: Gene-specific,Strength Instructions: Use GCK PS3 decision tree, which incorporates the relative activity index (RAI), relative stability index (RSI), and assays that measure the impact of variants on binding with GKRP and GKA. (Ref 5,6,7,12). For canonical splice site variants, do not use PS3 for RNA studies demonstrating abnormal splicing, since PVS1 will already be used at some level. To use PS3, functional study must have been performed on a transfected variant. If a study was performed on a cell line generated from a patient sample (and therefore contains the variant plus any other genomic variation the patient has) does not count as PS3. Not Applicable Comments: Studies performed on a cell line generated from a patient sample (which will be heterozygous and also contain other variants in the patient’s genome which could modify function) will not count as PS3 but instead will count toward PP4_Moderate. Note that although occurrence in the transactivation domain (codons 281-631, NM_000545.8 has been cited in older publications as evidence for causality, it is known that the transactivation domain is more tolerant to benign missense variation and therefore we will not apply PM1 at any level to variants within this region at this time (PMID: 11272211, 18003757, 23348805).
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 7 or more occurrences in unrelated individuals = Strong. Modification Type: Gene-specific,Strength Moderate 4-6 occurrences in unrelated individuals = Moderate. Modification Type: Gene-specific,Strength Supporting Instructions: Variant should meet PM2_Supporting in order to use PS4 at any level (careful review of gnomAD QC data may be necessary to assess whether variant is real or an artifact, especially if variant is in a polyC region). Phenotype of the patient must include diabetes, with evidence of an autoimmune etiology and/or absolute or near-absolute insulin deficiency considered as exclusionary: One or more positive diabetes autoantibodies (IA-2A, ZnT8A+, GAD) (Ref 15,16, 17, 18). Very low or negative C-peptide, defined as either fasting or non-fasting random C-peptide (<200pmol/L or 0.6ng/mL) (Ref 13, 14) or urinary C-peptide/creatinine ratio <0.2 nmol/mmol (Ref 16, 17) Not Applicable
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 Applicable for glucose- and ATP-binding sites (see attached chart). Modification Type: Gene-specific Supporting Instructions: See attached chart. 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 gnomAD 2.1.1 Popmax FAF ≤ 1:333,000 (≤ 0.000003 or 0.0003%) in European Non-Finnish population AND ≤ 2 copies observed in ENF AND ≤ 1 copy in any other founder or non-founder population. Modification Type: Gene-specific Instructions: Recommend using as supporting level of evidence (PM2_Supporting) per ClinGen guidance. Per guidance from ClinGen/SVI, PM2_Supporting + PVS1 is sufficient evidence of a variant being likely pathogenic. We recommend investigating the genotype metrics in gnomAD for variants that have been flagged for having failed one or more quality parameters, as it is possible that some of these filtered variants are actually real. The number of filtered alleles can be counted to determine whether PM2_Supporting would be met even if they were genuine calls. If the filtered calls are sufficient in number to not meet PM2_Supporting, then we would not use it. Because it is also possible that these calls are false positives, we would not use filtered variants to support BA1 or BS1. Allele frequency cutoffs using gnomAD 2.1.1. If there is a Popmax Filtering AF for both exomes and genomes, use that with the higher denominator. Not Applicable Comments: Per guidance from ClinGen/SVI, PM2_Supporting + PVS1 is sufficient evidence of a variant being likely pathogenic
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 Use SVI-recommended point-based system. Modification Type: Strength Strong Use SVI-recommended point-based system. Modification Type: Strength Moderate Use SVI-recommended point-based system. Modification Type: Strength Supporting Use SVI-recommended point-based system. Modification Type: Strength Instructions: Applicable for variants found in neonatal diabetes. Criterion can also be used to interpret the pathogenicity of a heterozygous variant (i.e., GCK-MODY) if the variant under assessment has also been identified in a patient with neonatal diabetes in the homozygous state or in trans with a P/LP variant or VUS). Not Applicable
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 For single amino acid deletions, use as supporting level of evidence. Modification Type: Strength Supporting For single amino acid deletions/insertions, use as supporting level of evidence Modification Type: Strength 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 Applicable once two amino acid changes have been classified as pathogenic at the same amino acid residue. Modification Type: Strength Moderate The novel amino acid change must have a Grantham distance greater than or equal to the previously classified pathogenic variant. Modification Type: Strength Supporting Apply if the previously classified amino acid change is likely pathogenic (rather than pathogenic) or if the previously classified variant is pathogenic but has a greater Grantham distance. Modification Type: Strength 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 Strong Moderate Supporting Not Applicable Comments: Subsumed in PS2.
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 Use thresholds suggested by Jarvik and Browning⁸ Single Family : ≤ 1/32 (5 meioses) >1 Family : ≤ 1/16 (4 meioses) Modification Type: General recommendation,Gene-specific Moderate Use thresholds suggested by Jarvik and Browning⁸ Single Family : ≤ 1/16 (4 meioses) >1 Family : ≤ 1/8 (3 meioses) Modification Type: General recommendation,Gene-specific Supporting Use thresholds suggested by Jarvik and Browning⁸ Single Family : ≤ 1/8 (3 meioses) >1 Family : ≤ ¼ (2 meioses) Modification Type: General recommendation,Gene-specific Instructions: Variable penetrance and phenocopies complicate co-segregation studies. The presence of type 1 and type 2 diabetes phenocopies and significance of variants in unaffected individuals as defined above will need to be considered. We expect to see hyperglycemia at birth in an individual with GCK-MODY and therefore consider an individual unaffected if euglycemic in childhood or adulthood. Since individuals typically do not present with symptoms of diabetes, a statement that someone is “nondiabetic” is insufficient to classify a family member as unaffected; fasting glucose must be tested and found to be within normal limits (<100 mg/dl = 5.5 mmol/L) or HbA1c test <=5.5% since the GCK range was 5.6 - 7.6% (Ref13). Presence of clinically significant diabetes complications in anyone with the variant is an exclusion. Not Applicable Comments: Phenotype of affected individuals must include diabetes, without clear evidence of an autoimmune etiology (see rules).
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 Apply to all missense variants in GCK. gnomAD missense constraint score for GCK is 3.07 (observed/expected= 0.5), which is significant. Modification Type: Gene-specific Not Applicable Comments: Missense variants account for 55% of all published pathogenic variants in this gene (Colclough et al 2013), however the constraint score for HNF1A (gene) is 1.07, which is not significant; therefore, we do not support using this criterion at this time. The low constraint score is most likely due to high tolerance for missense variants in the transactivation domain (see PM1 section). There are significantly more pathogenic missense variants in the DNA binding and dimerization domains, which are much less tolerant to missense variation. We may update this in the future if we can generate domain-specific scores.
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 Use REVEL score of ≥0.70 as supportive evidence of pathogenicity. We also support using SpliceAI to assess the predicted impact of non-canonical splicing variants and synonymous variants: apply PP3 when the predicted change is at least 0.2⁹,¹⁰ Modification Type: General recommendation 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 HbA1C 5.6 – 7.6% (38-60 mmol/mol) (if given multiple results, use maximum value) AND Fasting glucose 5.5-8 mmol/L (100-144 mg/dL) AND presence of any of the following additional features: PP4 phenotype found in pediatric patient (prepubertal or <10 years) (incidentally) AND Not treated with insulin AND antibody negative OR treated with insulin, antibody negative, and detectable C-peptide (> 0.6ng/mL) after 3 years Multiple values (= persistent)—multiple levels (>=2 counts) or well-documented persistent impaired fasting glucose (IFG) OGTT with minimal increment <3 mmol/l (54 mg/dl) Antibody negative Macrosomia in normoglycemic offspring of hyperglycemic gestational parent Low birthweight in hyperglycemic offspring of hyperglycemic gestational parent. Three-generation, dominant family history of diabetes or hyperglycemia (in a family not used for PP1) Modification Type: Gene-specific,Strength Supporting HbA1C 5.6 – 7.6% (38-60 mmol/mol) (if given multiple results, use maximum value) AND Fasting glucose 5.5-8 mmol/L (100-144 mg/dL) Modification Type: Gene-specific Instructions: Negative testing of other genes not necessary because phenotype is very specific. Sixty percent of patients with GCK-MODY phenotype will test positive.  There is a small chance that patient has HNF1A- or HNF4A-MODY in the early stages of disease (can get info about likelihood from family history).  About 1% of patients with GCK-MODY will have deletions or other variants (e.g., promoter) that are not identified via Sanger sequencing- consider testing via NGS or other technology. For patients tested because of neonatal diabetes, PP4 can be applied if there has been negative testing for major monogenic causes for neonatal diabetes. These include ABCC8, KCNJ11, and INS. In consanguineous cases, EIF2AK3 should be tested as well Not Applicable Comments: Phenotype of affected individuals must include diabetes, without clear evidence of an autoimmune etiology (see rules). Certain assumptions can be made in order to use the MODY probability calculator: * Specific clinical information about parents not given but lab/literature states “Family history of diabetes”: Click “Parent with diabetes” in calculator. * No information about family history of diabetes is provided: Attempt to use the calculator using both possibilities (yes/no). If this makes a difference in the ability to meet the PP4 cutoff (>50%), PP4 cannot be used. * Weight/Height/BMI not given but lab/literature states patient is “lean”: Enter BMI of 30. * HbA1c is not provided: Attempt to use the calculator using values of 6% and 10%. If this makes a difference in the ability to meet the PP4 cutoff (>50%), PP4 cannot be used. * Treatment information is not provided: Cannot use calculator.
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 gnomAD 2.1.1 Popmax Filtering AF ≥ 1:10,000 (≥ 0.01% or 0.0001). Modification Type: Gene-specific Very Strong Strong Moderate Supporting Instructions: Allele frequency cutoffs using gnomAD 2.1.1. If there is a Popmax Filtering AF for both exomes and genomes, use that with the higher denominator. 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 gnomAD 2.1.1 Popmax Filtering AF ≥ 1:25,000 (0.004% or 0.00004). Modification Type: Gene-specific Moderate Supporting Instructions: Allele frequency cutoffs using gnomAD 2.1.1. If there is a Popmax Filtering AF for both exomes and genomes, use that with the higher denominator. 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 We expect to see hyperglycemia at birth in an individual with _GCK_-MODY and therefore consider an individual unaffected if euglycemic in childhood or adulthood. Since individuals typically do not present with symptoms of diabetes, evidence that someone is “nondiabetic” is insufficient; fasting glucose must be tested and found to be within normal limits (<100 mg/dl / 5.6 mmol/L). Modification Type: Gene-specific Moderate Supporting 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 Applicable to non-canonical splice site variants that have RNA and in silico evidence of normal splicing (see BP4). Modification Type: Gene-specific Moderate Supporting Use GCK PS3 decision tree, which incorporates the relative activity index (RAI), relative stability index (RSI) and assays that measure the impact of variants on binding with GKRP and GKA. Evidence of no impact on function: Normal RAI (>0.5) + normal RSI (>0.5) + normal inhibition/activation with GKRP/GKA = BS3_Supporting Normal RAI (>0.5) + normal RSI (>0.5) but no studies investigating GKRP/GKA = Cannot use PS3 or BS3 Gloyn, et al. 2005 ⁵; Beer, et al. 2012 ⁶; Raimondo, et al. 2014 ⁷; Gloyn, et al. (2004)¹². Modification Type: Gene-specific Instructions: To use BS3, functional study must have been performed on a transfected variant. If a study was performed on a cell line generated from a patient sample (and therefore contains the variant plus any other genomic variants the patient has) it cannot count as BS3. Not Applicable Comments: To use BS3, functional study must have been performed on a transfected variant. If a study was performed on a cell line generated from a patient sample (and therefore contains the variant plus wild-type allele and other variants in the patient’s genome) it cannot count as BS3.
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 Applicable to family members without variant who meet PP4 criteria (HbA1C 5.6 – 7.6% (38-60 mmol/mol) (if given multiple results, use maximum value) AND Fasting glucose 5.5-8 mmol/L (100-144 mg/dL)) Modification Type: Gene-specific 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
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 Also applicable when in cis or trans with a likely pathogenic variant. Modification Type: General recommendation 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
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 Use a REVEL score of ≤0.15 as supportive evidence of no predicted impact on the gene or gene product. We also support using SpliceAI to assess the predicted impact of non-canonical splicing variants and synonymous variants: apply BP4 when the predicted change is below 0.2⁹,¹⁰. Modification Type: General recommendation 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 A variant in another monogenic diabetes gene is P/LP. Modification Type: General recommendation 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 Apply BP7 when the predicted change from SpliceAI is below 0.2 AND phyloP100 way < 2.0. Modification Type: Gene-specific Not Applicable

Files & Images

GCK PS3/BS3 Decision Tree: Monogenic Diabetes Variant Curation Expert Panel GCK PS3 and BS3 Decision Tree

GCK PM1 Residues: Amino acid residues in GCK for application of PM1

GCK Points Table for PM3 : Points table for applying PM3 (in trans) criteria for GCK

PS2 De Novo Points Table: Points table for determining strength of PS2 for apparent de novo variants

GCK PVS1 Decision Tree: Decision tree for determining strength of PVS1 for GCK variants

References

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