LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-11-06
Case ID: NM_000525.4_c.602G_A_20261106_051731
Framework: ACMG/AMP 2015
Variant classification summary

NM_000525.4:c.602G>A

KCNJ11  · NP_000516.3:p.(Arg201His)  · NM_000525.4
GRCh37: chr11:17409037 C>T  ·  GRCh38: chr11:17387490 C>T
Gene: KCNJ11 Transcript: NM_000525.4
Final call
Pathogenic
PS1 strong PS3 moderate PS4 strong PM1 moderate PM2 supporting PM5 moderate PP1 supporting PP3 strong
All criteria require review: For research and educational purposes only.
Variant details
Gene
KCNJ11
Transcript
NM_000525.4
Protein
NP_000516.3:p.(Arg201His)
gnomAD AF
0.0 (v4.1)
ClinVar
Pathogenic
OncoKB
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Pathogenic: PS1 strong supports the exact p.Arg201His substitution as previously disease-associated.
2
Pathogenic: PS3 moderate supports damaging KATP-channel and insulin-secretion effects in independent functional assays.
3
Pathogenic: PS4 strong supports significant enrichment in affected individuals compared with controls.
4
Pathogenic: PM1 moderate supports Arg201 as a KCNJ11 neonatal-diabetes hotspot.
5
Pathogenic: PM2 supporting supports absence from gnomAD v2.1 and v4.1.
6
Pathogenic: PM5 moderate supports other disease-associated missense substitutions at Arg201.
7
Pathogenic: PP1 supporting supports co-segregation in an affected mother-proband pair.
8
Pathogenic: PP3 strong supports a damaging computational prediction with REVEL 0.982.
Final determination: Under generic ACMG/AMP 2015 fallback rules, two strong pathogenic criteria alone support Pathogenic, and this variant additionally has three moderate and two supporting pathogenic criteria with no benign rule met.
Criteria assessment
ACMG/AMP criteria review
Criteria shown when status is available
All criteria require review: For research and educational purposes only.
Criterion Status Rationale Evidence used
PVS1 N/A Not applicable: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.
pvs1_generic_framework generic_acmg_combination_rules
PS1 Met Met: the exact p.Arg201His change was reported in 11 families and 14 patients and independently characterized in functional studies.
PMID:15448106 PMID:15718250 PMID:16609879 PMID:17065345
PS2 Not met Not met: the variant was reported in both a proband and her affected mother, demonstrating inheritance rather than confirmed de novo occurrence.
PMID:15448106
PS3 Met Met at moderate strength: independent beta-cell, mammalian-cell, and oocyte assays consistently showed R201H reduced ATP sensitivity, surface expression, electrical activation, and insulin secretion.
PMID:16731837 PMID:17065345 PMID:15718250
PS4 Met Met: one R201H carrier among 11 probands versus 0/100 controls gave continuity-corrected OR 28.7 (95% CI 1.10-750.38), exceeding OR >5 with CI excluding 1.
PMID:15448106 PMID:16609879
PM1 Met Met: Arg201 is explicitly identified as a neonatal-diabetes hotspot, and R201H is absent from gnomAD v2.1 and v4.1.
PMID:27681997 gnomad_v2 gnomad_v4
PM2 Met Met at supporting strength: AF is 0 in gnomAD v2.1 (0/248,530) and v4.1 (0/1,612,208), below the <=0.0001 PM2 threshold.
gnomad_v2 gnomad_v4 PMID:25741868
PM3 Not assessed Not assessed: no second pathogenic allele or parental/offspring testing establishes that KCNJ11 p.Arg201His is in trans.
PMID:15448106
PM4 N/A Not applicable: PM4 requires a protein-length change, and this is a missense variant.
pvs1_generic_framework generic_acmg_combination_rules
PM5 Met Met: different missense substitutions at Arg201, including R201C and R201L, were reported in KCNJ11 neonatal diabetes.
PMID:27681997
PM6 Not assessed Not assessed: available primary evidence shows maternal transmission, and no qualifying assumed-de novo case with undocumented parental confirmation is sufficiently documented.
PMID:15448106
PP1 Met Met at supporting strength: p.Arg201His co-segregated with permanent neonatal diabetes in the affected proband and her affected mother.
PMID:15448106
PP2 Not assessed Not assessed: missense disease mechanism is established, but no gene-level evidence or threshold demonstrates a low rate of benign missense variation.
PMID:16609879 gnomad_v2 gnomad_v4
PP3 Met Met, strong: missense REVEL 0.982 exceeds the supplied PP3 strong threshold of 0.932.
revel
PP4 Not met Not met: neonatal diabetes has multiple genetic etiologies, so the phenotype is not highly specific for a single genetic cause under PP4.
PMID:16609879 PMID:27681997
PP5 Not met Not met: ClinVar has no exact-variant expert-panel classification, so clinical-laboratory and aggregate Pathogenic assertions cannot trigger PP5.
clinvar
BA1 Not met Not met: gnomAD observed AF is 0/1,612,208 alleles, far below the >=5% BA1 threshold.
gnomad_v2 gnomad_v4 clinvar PMID:25741868
BS1 Not met Not met: observed AF is 0/1,612,208 alleles, with no elevated filtering frequency exceeding the generic 1% BS1 default.
gnomad_v2 gnomad_v4
BS2 Not met Not met: gnomAD shows 0 alternate alleles and 0 homozygotes, with no healthy-adult observation of R201H.
gnomad_v2 gnomad_v4 PMID:15448106 PMID:16609879
BS3 Not met Not met: independent assays showed R201H reduced ATP sensitivity and surface expression and impaired beta-cell electrical activity and insulin secretion, rather than no damaging effect.
PMID:16731837 PMID:17065345 PMID:15718250
BS4 Not assessed Not assessed: no affected relative lacking the variant is documented, so lack of segregation cannot be established.
PMID:15448106
BP1 Not met Not met: affected cohorts contain numerous pathogenic activating missense variants, with no evidence that KCNJ11 disease is primarily truncating.
PMID:16609879 PMID:27681997
BP2 Not assessed Not assessed: no documented pathogenic variant in trans or cis with KCNJ11 p.Arg201His is available for BP2 evaluation.
PMID:15448106
BP3 N/A Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.
pvs1_generic_framework generic_acmg_combination_rules
BP4 Not met Not met: missense REVEL 0.982 is above the most permissive supplied BP4 threshold of 0.29.
revel
BP5 Not assessed Not assessed: the available reports do not establish an alternate molecular basis for disease in a case carrying KCNJ11 R201H.
PMID:15448106 PMID:16609879 PMID:27681997
BP6 Not met Not met: no exact-variant ClinVar expert-panel Benign or Likely benign classification is present to satisfy BP6.
clinvar
BP7 N/A Not applicable: BP7 requires a synonymous variant, and this is a missense variant.
generic_acmg_combination_rules
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