The ELP1 NM_003640.5:c.2204+6T>C (NP_003631.2:p.?) intronic variant has not previously been reported in somatic cancers (COSMIC). Experimental evidence: Four independent variant-specific studies reproduced exon 20 skipping with reduced full-length ELP1/IKAP transcript or protein in patient cells and minigene assays. Based on available guidelines, this variant is considered to be Pathogenic.
Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.
Pathogenic.A pathogenic classification under the recorded framework.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.ELP1 encodes a scaffold protein that helps assemble kinase complexes involved in inflammatory signaling, including activation of NF-kappa-B. Changes in ELP1 cause familial dysautonomia, a hereditary disorder affecting the autonomic and sensory nervous systems. ELP1 is not currently established as a cancer-associated gene.
The recorded framework is Generic ACMG/AMP 2015 with ClinGen SVI recommendations. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
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.
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.
Met: affected probands carried c.2204+6T>C in trans with R696P, with each allele inherited from a different heterozygous parent in two families.
Met at supporting: SpliceAI maximum delta 0.06 meets the generic BP4 threshold of <=0.1.
Pathogenic: PS3 (strong) plus PS4 (strong) satisfy the generic ACMG/AMP 2-Strong rule, with PM3 (moderate) as additional evidence; BP4 alone does not meet a benign rule.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 635 / 1,611,286 alleles. Recorded AF 0.000394095. Recorded homozygote count 0.
This variant is present in gnomAD v2.1 (AF= 0.000615611; MAF= 0.06156%, 174/282646 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.0134118; MAF= 1.34118%, 139/10364 alleles, homozygotes = 0); grpmax FAF= 0.00015987.
Not available in gnomAD-Canada v1.0.
Recorded SpliceAI maximum delta score: 0.060. Refer to the recorded PP3/BP4 rationale for interpretation.
20 Pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
No standalone functional evidence summary is recorded in evidence_summary.functional.
This variant has not previously been reported in somatic cancers (COSMIC).
ACMG/AMP criteria under Generic ACMG/AMP 2015 with ClinGen SVI recommendations, with the data and sources behind each one.
28 criteria with recorded statuses: 4 met · 11 not met · 4 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Under generic ACMG/AMP definitions, PVS1, PM4, and BP3 are not applicable to this non-canonical intronic +6 substitution; variant-specific splicing evidence does not change the named variant-type limits of these criteria.
All five requested codon/residue/domain criteria are not applicable because the evaluated variant is an intronic splice-region substitution with protein consequence p.?, not a missense or other residue-defined protein change.
The available evidence supports inherited transmission from carrier parents in affected recessive cases, not de novo occurrence.
No qualifying family pedigrees establish PP1 co-segregation or BS4 lack of segregation.
PS4 is met because affected-proband and population-control data show extreme enrichment, with a computed OR of 1815.55 and 95% CI 108.27–30444.54.
PP4 remains not assessed because the case-specific phenotype and family history are not documented.
PP5 and BP6 are not met because the exact-variant ClinVar record has no expert-panel classification; BP5 is not assessed because no alternate molecular basis is documented.
The variant is intronic/splice-region, so PP3 and BP4 were adjudicated exclusively through SpliceAI; no REVEL or BayesDel evidence was used.
SpliceAI maximum delta 0.06 is below the PP3 supporting cutoff of 0.2 and meets the BP4 supporting cutoff of 0.1.
BP7 is not applicable because the variant is not synonymous.
No criteria match.
Multiple independent, variant-specific functional studies support a damaging splice effect for NM_003640.5:c.2204+6T>C (ELP1; historically IKBKAP/IKAP). Patient-derived tissues and cells show tissue-dependent exon 20 skipping, reduced full-length transcript and protein, and the original molecular study demonstrated exon 20 exclusion with a frameshift and truncated protein. Minigene assays independently reproduced preferential exon 20 skipping and linked it to weakened 5′ splice-site activity. Patient-derived olfactory ecto-mesenchymal stem cells confirmed aberrant exon 20 inclusion/skipping and reduced IKAP/hELP1 synthesis. The evidence is biologically relevant, variant-specific, replicated across orthogonal assay systems, and includes disease-relevant patient material; it supports PS3 at strong strength. No benign functional result was identified, and the therapeutic rescue experiments do not negate the baseline damaging effect.
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
PS4 is met. Anderson et al. (PMID:11179021) reported 31 affected familial-dysautonomia probands homozygous for the intron-20 +6 T>C mutation and 27 carriers among 819 random Ashkenazi Jewish controls. Treating affected-proband carrier status as the case phenotype comparison, a Haldane-corrected 2x2 calculation gives OR=1815.55, 95% CI 108.27-30444.54; the interval excludes 1 and OR >5.0. This is a case-control comparison even though the paper did not print an odds ratio. The same variant was reported in >99.5% of affected Ashkenazi Jewish FD alleles, while Dong et al. found 80 carriers among 2,518 anonymous controls (3.2%), independently supporting marked enrichment.
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. ... 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.
Familial dysautonomia is explicitly described as autosomal recessive. In two families, affected probands carried the major FD splice allele, corresponding to NM_003640.5:c.2204+6T>C, and the pathogenic R696P allele on the other chromosome: one parent and the proband were heterozygous for R696P, while the other parent and the proband were heterozygous for 2507+6T>C. This establishes the evaluated variant in trans with a disease-associated second allele through parental testing. The same study also reported affected individuals homozygous for the splice variant, but the compound-heterozygous observations provide the decisive PM3 evidence.
For recessive disorders, detected in trans with a pathogenic variant ... Note: This requires testing of parents (or offspring) to determine phase.
This is an intronic splice-region variant, so the generic rule requires the SpliceAI path only; REVEL is not applicable and is not used. SpliceAI reports a maximum delta score of 0.06, which is <=0.1 and therefore meets the generic BP4 supporting threshold from the ClinGen SVI SpliceAI calibration (Jaganathan et al. 2019, PMID:30661751). This computational result is limited to the splice-impact path and is not used to negate the independently reported functional splice effect.
BP4: Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
PS2 is not met. The available variant-specific family data do not show a de novo occurrence with confirmed maternity and paternity; instead, the study reports 31 probands homozygous for the familial dysautonomia-associated intron 20 +6 variant and all parents heterozygous, demonstrating transmission from carrier parents rather than a de novo event. No evidence of absent family history for a qualifying de novo proband is provided.
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
PM2 is not met. Under the generic default, the variant is present at AF 0.000615611 in gnomAD v2.1 and AF 0.000394095 in gnomAD v4.1, both above the supplied PM2 threshold of 0.0001. The available non-cancer subsets are also above threshold: gnomAD v2.1 non-cancer exomes AF 0.000654749 and gnomAD v3.1 non-cancer genomes AF 0.000500047. No VCEP specifies a non-cancer or exome-only source for this generic interpretation.
Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
PM6 is not met. The available variant-specific family data do not support an assumed de novo occurrence without parental confirmation; the study instead reports 31 homozygous probands and heterozygous parents, consistent with inherited transmission from carrier parents. No proband is documented as carrying a newly arising variant without confirmed maternity and paternity.
Assumed de novo, but without confirmation of paternity and maternity.
This is an intronic splice-region variant, so the generic rule requires the SpliceAI path only; REVEL is not applicable and is not used. SpliceAI is available and reports a maximum delta score of 0.06. This is below the generic PP3 supporting threshold of >=0.2 from the ClinGen SVI SpliceAI calibration (Jaganathan et al. 2019, PMID:30661751), so PP3 is not met. Variant-specific computational splice analyses reported by PMID:16964593 were reviewed but do not replace the governing SpliceAI threshold or justify double-counting another computational path.
PP3: Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
PP5 is not met under the required generic rule. ClinVar variation 6085 reports Pathogenic with multiple submitters, but the audit records zero expert-panel submissions; the available assertions are ordinary laboratory or other non-expert submissions. Literature reporting the variant as disease-causing cannot substitute for the required exact-variant ClinVar expert-panel classification.
Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.
BA1 is not met. The required filtering allele-frequency measure is grpmax FAF, not the Ashkenazi Jewish popmax point estimate. gnomAD v2.1 reports grpmax FAF 0.00015987 and gnomAD v4.1 reports grpmax FAF 0.00006061, both below the generic stand-alone threshold of 0.05. The Ashkenazi Jewish popmax point estimates of 0.0134118 and 0.0157190 are not substitutes for FAF; the variant is also a documented familial-dysautonomia founder allele with a pathogenic ClinVar consensus and a reported Ashkenazi Jewish carrier frequency of 3.2%.
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
BS1 is not met. Using the required filtering allele-frequency measure, grpmax FAF is 0.00015987 in gnomAD v2.1 and 0.00006061 in gnomAD v4.1, both below the generic BS1 default threshold of 0.01. The elevated Ashkenazi Jewish popmax point estimates are not eligible substitutes for FAF. The disorder is autosomal recessive with a known Ashkenazi Jewish founder allele and a reported carrier frequency of 3.2%, so the ancestry-enriched point estimate is not by itself evidence that the allele is more frequent than expected for familial dysautonomia.
Allele frequency is greater than expected for the disorder.
BS2 is not met. gnomAD v2.1 and gnomAD v4.1 each report zero homozygotes for the variant, and no healthy adult homozygote is documented. Available clinical reports describe affected homozygous individuals, not healthy adults, so the healthy-adult requirement is not satisfied for this early-onset recessive disorder.
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.
BS3 is not supported. The available variant-specific functional evidence consistently demonstrates abnormal splicing and reduced ELP1/IKAP expression or a truncated product, rather than showing no damaging effect on protein function or splicing. The variant is therefore incompatible with application of this benign functional criterion.
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
The available family data show the evaluated splice variant in trans with R696P in affected individuals, not in cis. The disorder is explicitly autosomal recessive, so the trans observation does not satisfy the BP2 path restricted to a fully penetrant dominant gene/disorder; no cis observation with a pathogenic variant is reported. Therefore BP2 is not met.
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.
BP6 is not met under the required generic rule. ClinVar variation 6085 has no exact-variant expert-panel classification as Benign or Likely benign; the available record is Pathogenic from non-expert/laboratory submissions, and no qualifying benign expert-panel assertion is present.
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
PP1 cannot be assessed from the available evidence. The study documents multiple affected probands and carrier parents, but it does not provide pedigrees showing co-segregation of the variant with disease in multiple affected family members. The reported parent-genotype data establish transmission in recessive cases but do not satisfy the specified affected-family-member segregation requirement or support a PP1 strength level.
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
The literature describes familial dysautonomia as a clinically distinctive disorder with characteristic autonomic, sensory, gastrointestinal, and cardiovascular findings, and reports this variant in affected patients. However, the case bundle does not provide this patient's phenotype or family history, so the patient's phenotype cannot be judged highly specific under PP4.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
BS4 cannot be assessed. No affected family member who lacks the variant is documented, and no family-level non-segregation analysis or pedigree is available. The presence of heterozygous parents of homozygous affected probands is expected for a recessive condition and is not evidence of lack of segregation in affected members.
Lack of segregation in affected members of a family.
No evidence in the supplied case materials establishes that this variant was found in a case with an alternate molecular basis for disease. The available familial-dysautonomia literature and ClinVar records do not document an alternate molecular diagnosis for an individual carrying this variant.
Variant found in a case with an alternate molecular basis for disease.
The variant is NM_003640.5:c.2204+6T>C, a non-canonical intronic +6 splice-position variant rather than a nonsense, frameshift, canonical +/-1 or 2 splice-site, initiation-codon, or single/multi-exon-deletion variant named by the generic PVS1 definition. Variant-specific studies show exon 20 skipping, reduced full-length ELP1/IKAP, and in one report a frameshifted truncated protein, while the ELP1 loss-of-function disease mechanism is supported; however, those functional consequences do not expand the generic PVS1 variant-type/location rule to non-canonical +6 variants.
PVS1: 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.
Not applicable: the variant is NM_003640.5:c.2204+6T>C, an intronic splice-region substitution with protein consequence p.? rather than an amino-acid change, so the same-amino-acid criterion and its protein-level comparison cannot be applied.
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. ... Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
Not applicable: PM1 is a protein-region criterion for a variant located in a mutational hot spot or critical functional domain, whereas this variant is intronic at c.2204+6 and has no defined amino-acid residue or protein-domain location.
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.
The variant is an intronic splice-altering substitution, not an in-frame deletion, in-frame insertion, or stop-loss variant. Although exon 20 skipping can produce a shorter transcript and truncated protein, the generic PM4 definition is limited to the explicitly named protein-length-change classes and does not apply to this splice-mediated consequence.
PM4: Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
Not applicable: PM5 requires a novel missense change at an amino-acid residue where a different pathogenic missense change has been observed; this variant is intronic and has protein consequence p.?.
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. ... Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
Not applicable: PP2 explicitly applies to a missense variant, but NM_003640.5:c.2204+6T>C is an intronic splice-region variant with protein consequence p.?.
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
Not applicable: BP1 explicitly applies to a missense variant, but NM_003640.5:c.2204+6T>C is an intronic splice-region variant with protein consequence p.?.
Missense variant in a gene for which primarily truncating variants are known to cause disease.
The variant is an intronic single-nucleotide substitution and is not an in-frame deletion or insertion. Therefore, the generic BP3 repetitive-region criterion does not apply; no repeat-region context is relevant to the criterion's named variant class.
BP3: In frame-deletions/insertions in a repetitive region without a known function.
BP7 applies only to a synonymous variant. NM_003640.5:c.2204+6T>C is an intronic +6 splice-region variant, not a synonymous coding variant, so BP7 is not applicable regardless of its SpliceAI score.
BP7: 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.
Every interpreted variant in ELP1, mapped onto the exon structure of NM_003640.5. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| Ashkenazi Jewish465 / 29,582 | 0.016 |
| Remaining individuals78 / 62,392 | 0.0013 |
| European (non-Finnish)87 / 1,177,480 | 7.4e-05 |
| Admixed American3 / 60,008 | 5e-05 |
| European (Finnish)1 / 64,024 | 1.6e-05 |
| African/African American1 / 74,890 | 1.3e-05 |
| Ashkenazi Jewish139 / 10,364 | 0.013 |
| Remaining individuals7 / 7,220 | 0.00097 |
| European (non-Finnish)27 / 129,012 | 0.00021 |
| Admixed American1 / 35,420 | 2.8e-05 |
This variant is present in gnomAD v4.1 (AF= 0.000394095; MAF= 0.03941%, 635/1611286 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.015719; MAF= 1.57190%, 465/29582 alleles, homozygotes = 0); grpmax FAF= 6.061e-05.
This variant is present in gnomAD v2.1 (AF= 0.000615611; MAF= 0.06156%, 174/282646 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.0134118; MAF= 1.34118%, 139/10364 alleles, homozygotes = 0); grpmax FAF= 0.00015987.
Not available in gnomAD-Canada v1.0.
This is an intronic splice-region variant, so the generic rule requires the SpliceAI path only; REVEL is not applicable and is not used. SpliceAI reports a maximum delta score of 0.06, which is <=0.1 and therefore meets the generic BP4 supporting threshold from the ClinGen SVI SpliceAI calibration (Jaganathan et al. 2019, PMID:30661751). This computational result is limited to the splice-impact path and is not used to negate the independently reported functional splice effect.
BP4: Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
This is an intronic splice-region variant, so the generic rule requires the SpliceAI path only; REVEL is not applicable and is not used. SpliceAI is available and reports a maximum delta score of 0.06. This is below the generic PP3 supporting threshold of >=0.2 from the ClinGen SVI SpliceAI calibration (Jaganathan et al. 2019, PMID:30661751), so PP3 is not met. Variant-specific computational splice analyses reported by PMID:16964593 were reviewed but do not replace the governing SpliceAI threshold or justify double-counting another computational path.
PP3: Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
BP7 applies only to a synonymous variant. NM_003640.5:c.2204+6T>C is an intronic +6 splice-region variant, not a synonymous coding variant, so BP7 is not applicable regardless of its SpliceAI score.
BP7: 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.
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06).
8 paper records listed. 5 cited in the classification.
The normal donor splice sequence is GTAAGTG; the FD sequence is GTAAGCG.
Location Results, paragraphs describing IKAP intron 20; Figures 1 and 2
Context IKAP/ELP1 RT-PCR and cDNA sequencing, splice-site DNA sequencing, Western blot analysis, family segregation analysis, and Ashkenazi Jewish population screening.
The IVS20þ6T ! C mutation appears to result in exon skipping, but the amount of the abnormally spliced transcript appears to vary in different tissues.
Location Introduction; Results and Discussion; Table I
Context Carrier screening of 2,518 anonymous Ashkenazi Jewish individuals with sequencing confirmation and cited fibroblast transcript observations from affected individuals.
The c.220416T4C FD mutation in IKBKAP results in exon 20 skipping.
Location Abstract; Results, Computational Analysis of the FD and Normal Exon 20 5′ss; Figures 2–7
Context Computational splice-site analysis; IKBKAP minigene constructs spanning exons 19–21; coupled transcription/splicing assays using HeLa-S3 nuclear extract; transient transfection and RT-PCR in HEK293 cells; RNA oligonucleotide experiments.
Three FD-causing mutations have been identified to date in the IKBKAP gene: an intronic noncoding point mutation, IVS20+6T>C (c.2204+6T>C, NM_003640.2), which leads to variable skipping of exon 20, and two missense mutations, R696P (four patients) and P914L (one non-Jewish patient) [17–19].
Location Introduction, paragraph describing the three FD-causing mutations in IKBKAP
Context FD patient, carrier, and control lymphoblast cell lines; fibroblast observations; minigene splicing assays; quantitative RT-PCR; Western blot; and kinetin treatment experiments.
The most common mutation is a c.2204+6T>C transition in the 5′ splice site (5′ss) of IKBKAP intron 20, which causes a tissue-specific skipping of exon 20
Location Abstract; Introduction; Results, IKBKAP Splice Variants Ratio is Affected by Culture Conditions and Kinetin in FD hOE-MSCs
Context Patient-derived olfactory ecto-mesenchymal stem cells from five familial dysautonomia patients and five controls, with RT-PCR, RT-qPCR, microarray analysis, and kinetin treatment.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
This variant is present in gnomAD v4.1 (AF= 0.000394095; MAF= 0.03941%, 635/1611286 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.015719; MAF= 1.57190%, 465/29582 alleles, homozygotes = 0); grpmax FAF= 6.061e-05.
This variant is present in gnomAD v2.1 (AF= 0.000615611; MAF= 0.06156%, 174/282646 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.0134118; MAF= 1.34118%, 139/10364 alleles, homozygotes = 0); grpmax FAF= 0.00015987.
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Pathogenic (20 clinical laboratories). (ClinVarID = 6085)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06).
This variant has not previously been reported in somatic cancers (COSMIC).