LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-11-05
Case ID: NM_003640.5_c.2204_6T_C_20261105_031755
Framework: ACMG/AMP 2015
Variant classification summary

NM_003640.5:c.2204+6T>C

ELP1  · NP_003631.2:p.?  · NM_003640.5
GRCh37: chr9:111662096 A>G  ·  GRCh38: chr9:108899816 A>G
Gene: ELP1 Transcript: NM_003640.5
Final call
Pathogenic
PS3 strong PS4 strong PM3 moderate BP4 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
ELP1
Transcript
NM_003640.5
Protein
NP_003631.2:p.?
gnomAD AF
0.0003940951513263319 (v4.1)
ClinVar
Pathogenic
OncoKB
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Pathogenic: PS3 (strong) is supported by replicated variant-specific exon 20 skipping and reduced ELP1/IKAP expression.
2
Pathogenic: PS4 (strong) is supported by extreme affected-case enrichment, with OR 1815.55 and 95% CI 108.27–30444.54.
3
Pathogenic: PM3 (moderate) is supported by confirmed trans inheritance with the disease-associated R696P allele.
4
BP4 (supporting) is met by SpliceAI maximum delta 0.06 but does not independently satisfy a benign rule.
Final determination: Under the generic ACMG/AMP 2015 fallback, two strong pathogenic criteria (PS3 and PS4) satisfy the 2 Strong Pathogenic rule; BP4 alone does not satisfy a benign rule.
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: c.2204+6T>C is a non-canonical +6 intronic variant, outside generic PVS1's explicitly listed nonsense, frameshift, canonical +/-1 or 2, initiation-codon, and exon-deletion classes.
PMID:11179021 PMID:12116234 PMID:17206408 PMID:22190446
PS1 N/A Not applicable: c.2204+6T>C is an intronic splice-region variant with protein consequence p.?, not a defined amino-acid substitution.
PS2 Not met Not met: 31 homozygous probands had heterozygous parents, demonstrating inherited transmission rather than a confirmed de novo occurrence.
PMID:11179021
PS3 Met Met (strong): four independent variant-specific studies reproduced exon 20 skipping with reduced full-length ELP1/IKAP transcript or protein in patient cells and minigene assays.
PMID:11179021 PMID:16964593 PMID:17206408 PMID:22190446
PS4 Met Met: affected-proband versus control counts produced a continuity-corrected OR 1815.55 (95% CI 108.27–30444.54), exceeding 5.0 with the interval excluding 1.
PMID:11179021 PMID:12116234
PM1 N/A Not applicable: c.2204+6T>C is intronic with p.?, so no amino-acid residue can be evaluated against a protein hotspot or functional domain.
PM2 Not met Not met: gnomAD v4.1 all-comers AF is 0.000394095, exceeding the 0.0001 PM2 threshold, with similar non-cancer frequencies.
gnomad_v2 gnomad_v4
PM3 Met Met: affected probands carried c.2204+6T>C in trans with R696P, with each allele inherited from a different heterozygous parent in two families.
PMID:11179021 PMID:12116234
PM4 N/A Not applicable: the variant is an intronic splice substitution, not a generic PM4-eligible in-frame deletion, in-frame insertion, or stop-loss variant.
PMID:11179021 PMID:12116234 PMID:17206408 PMID:22190446
PM5 N/A Not applicable: PM5 requires a missense change at a defined residue, but c.2204+6T>C is intronic and has protein consequence p.?.
PM6 Not met Not met: 31 homozygous probands had heterozygous parents, supporting inherited transmission rather than an assumed de novo event.
PMID:11179021
PP1 Not assessed Not assessed: multiple probands and carrier parents are reported, but no pedigrees show co-segregation in multiple affected family members.
PMID:11179021
PP2 N/A Not applicable: PP2 is restricted to missense variants, while c.2204+6T>C is an intronic splice-region change with p.?.
PP3 Not met Not met: SpliceAI maximum delta 0.06 is below the generic PP3 supporting threshold of 0.2.
spliceai
PP4 Not assessed Not assessed: familial dysautonomia is clinically specific in the literature, but this case lacks a documented patient phenotype or family history.
PMID:12116234 PMID:11179021
PP5 Not met Not met: ClinVar has no expert-panel classification for this exact variant, only non-expert or laboratory submissions.
clinvar
BA1 Not met Not met: gnomAD v4.1 grpmax FAF is 0.00006061, far below the 0.05 BA1 threshold despite a 1.57% Ashkenazi Jewish popmax.
gnomad_v2 gnomad_v4 clinvar PMID:12116234
BS1 Not met Not met: gnomAD v4.1 grpmax FAF is 0.00006061 versus the 0.01 BS1 default, while the higher ancestry point estimate reflects a recessive founder allele.
gnomad_v2 gnomad_v4 PMID:12116234
BS2 Not met Not met: gnomAD v2.1 and v4.1 report zero homozygotes, with no healthy adult homozygote documented for this early-onset recessive disorder.
gnomad_v2 gnomad_v4 PMID:11179021
BS3 Not met Not met: all four variant-specific functional studies showed exon 20 skipping with reduced full-length ELP1/IKAP transcript or protein, not normal splicing or function.
PMID:11179021 PMID:16964593 PMID:17206408 PMID:22190446
BS4 Not assessed Not assessed: no affected non-carriers or family-level non-segregation data are documented for this variant.
BP1 N/A Not applicable: BP1 is restricted to missense variants, while c.2204+6T>C is an intronic splice-region change with p.?.
BP2 Not met Not met: the documented configuration is trans in an autosomal-recessive disorder, with no reported cis pathogenic-variant observation.
PMID:11179021 PMID:12116234
BP3 N/A Not applicable: c.2204+6T>C is an intronic single-nucleotide substitution, not an in-frame deletion or insertion in a repetitive region.
BP4 Met Met at supporting: SpliceAI maximum delta 0.06 meets the generic BP4 threshold of <=0.1.
spliceai
BP5 Not assessed Not assessed: no alternate molecular basis for disease is documented in a case carrying this variant.
BP6 Not met Not met: no exact-variant ClinVar expert-panel classification as benign or likely benign is present.
clinvar
BP7 N/A Not applicable: c.2204+6T>C is intronic, whereas BP7 is restricted to synonymous variants.
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