rs111033171

Positions:

• chr9-108899816-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP4

The NM_003640.5(ELP1):​c.2204+6T>C variant causes a splice donor region, intron change. The variant allele was found at a frequency of 0.000394 in 1,611,286 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00051 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00038 (0 hom.)
• Consequence: ELP1 NM_003640.5 splice_donor_region, intron
• Scores: Splicing: ADA: 0.6565
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:17 U:1 O:2
• Conservation: PhyloP100: 4.01

Genes affected

ELP1 (HGNC:5959): (elongator acetyltransferase complex subunit 1) The protein encoded by this gene is a scaffold protein and a regulator for three different kinases involved in proinflammatory signaling. The encoded protein can bind NF-kappa-B-inducing kinase and I-kappa-B kinases through separate domains and assemble them into an active kinase complex. Mutations in this gene have been associated with familial dysautonomia. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-108899816-A-G is Pathogenic according to our data. Variant chr9-108899816-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 6085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-108899816-A-G is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ELP1	NM_003640.5	c.2204+6T>C		splice_donor_region_variant, intron_variant		ENST00000374647.10	NP_003631.2
ELP1	NM_001318360.2	c.1862+6T>C		splice_donor_region_variant, intron_variant			NP_001305289.1
ELP1	NM_001330749.2	c.1157+6T>C		splice_donor_region_variant, intron_variant			NP_001317678.1
ELP1	XM_047423991.1	c.2204+6T>C		splice_donor_region_variant, intron_variant			XP_047279947.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ELP1	ENST00000374647.10	c.2204+6T>C		splice_donor_region_variant, intron_variant		1	NM_003640.5	ENSP00000363779	P1

Frequencies

GnomAD3 genomes AF: 0.000506 AC: 77 AN: 152236 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000649 AC: 163 AN: 251240 Hom.: 0 AF XY: 0.000626 AC XY: 85 AN XY: 135788

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.0129

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000229

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000382 AC: 558 AN: 1459050 Hom.: 0 Cov.: 30 AF XY: 0.000408 AC XY: 296 AN XY: 726186

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.0153

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000739

Gnomad4 OTH exome AF: 0.00124

GnomAD4 genome AF: 0.000506 AC: 77 AN: 152236 Hom.: 0 Cov.: 32 AF XY: 0.000551 AC XY: 41 AN XY: 74372

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.0190

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00144

Alfa AF: 0.000966 Hom.: 0

Bravo AF: 0.000442

EpiCase AF: 0.000218

EpiControl AF: 0.000296

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17 Uncertain:1 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial dysautonomia Pathogenic:10 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2007	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
not provided, no classification provided	literature only	GeneReviews	-	Founder variant that accounts for >99.5% of pathogenic variants in Ashkenazi Jews -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 21, 2017	Variant summary: The IKBKAP c.2204+6T>C variant involves the alteration of a conserved intronic nucleotide. MutationTaster predicts a damaging outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing. However, multiple splicing studies have shown that this variant causes skipping of exon 20 (Slaugenhaupt_2001; Anderson_2001). This variant was found in 93/122048 control chromosomes at a frequency of 0.000762, which does not exceed the estimated maximal expected allele frequency of a pathogenic IKBKAP variant (0.001838). The variant is a common pathogenic variant found in the Askenazi Jewish population as a founder mutation. A carrier rate as high as 1 in 32 has been reported in this population (Dong_2002). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Oct 18, 2019	NM_003640.3(IKBKAP):c.2204+6T>C is classified as pathogenic in the context of familial dysautonomia. Sources cited for classification include the following: PMID 11179008, 22850346, 16964593, 11179021, 17206408. Classification of NM_003640.3(IKBKAP):c.2204+6T>C is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 30, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Nov 30, 2018	The IKBKAP c.2204+6T>C variant, also referred to as IVS20+6T>C, is a well-known pathogenic variant for familial dysautonomia (FD). The carrier frequency of this variant is 3.2% in FD patients of Ashkenazi Jewish descent, accounting for approximately 99% of disease alleles in this ethnic group (Dong et al. 2002; Shohat et al. 2014). In one study the c.2204+6T>C variant was found in 38 homozygotes and 2 compound heterozygotes all affected with familial dysautonomia (Anderson et al. 2001). The c.2204+6T>C variant has been reported at a frequency of 0.013900 in the Ashkenazi Jewish population of the Genome Aggregation Database. The c.2204+6T>C variant has been shown to affect mRNA splicing and cause tissue-specific skipping of exon 20, which leads to changes in neuronal gene expression and development (Slaugenhaupt et al. 2001; Anderson et al. 2001; Boone et al. 2012). Based on the collective evidence, the c.2204+6T>C variant is classified as pathogenic for familial dysautonomia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NG_008788.1(NM_003640.3):c.2204+6T>C (IVS20+6T>C) in the ELP1 gene has an allele frequency of 0.013 in Ashkenazi Jewish subpopulation in the gnomAD database. The c.2204+6T>C splice site variant in the ELP1 gene has been previously reported as a founder mutation in the Ashkenazi Jewish population with a reported carrier frequency of 1 in 36 individuals (PMID: 11179008). Anderson et al. reported 38 homozygotes and 2 compound heterozygotes of this variant in patients with familial dysautonomia (PMID: 11179021). Splicing study demenstrated that normal splicing of the IKAP transcript results in removal of introns 19 and 20 and in retention of exon 20. In comparison, c.2204+6T>C in the donor splice site of intron 20 in the mutant allele results in removal of introns 19 and 20 and exon 20 (PMID: 11179021). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PS4; PS3; PM3_Strong. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 25, 2019	The c.2204+6T>C variant in IKBKAP has been reported in several individuals with familial dysautonomia and is a founder mutation in the Ashkenazi Jewish population (Slaugenhaupt 2001, Anderson 2001). This variant has been identified in 1.3% (139/10364) of Ashkenazi Jewish chromosomes and 0.003% (27/129012) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and is reported in ClinVar (Variation ID: 6085). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant is located in the 5' splice region and was demonstrated to lead to aberrant splicing in vitro (Ibrahim 2007). In summary, this variant meets criteria to be classified as pathogenic for familial dysautonomia in an autosomal recessive manner based upon its biallelic occurrence in cases and demonstrated impact on splicing. ACMG/AMP Criteria applied: PM3_VeryStrong, PP3, PS3_Supporting. -

not provided Pathogenic:5 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change falls in intron 20 of the ELP1 gene. It does not directly change the encoded amino acid sequence of the ELP1 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs111033171, gnomAD 1.4%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individual(s) with familial dysautonomia (FD) (PMID: 11179021, 12116234). It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 11179008, 11179021, 12116234, 20301359). ClinVar contains an entry for this variant (Variation ID: 6085). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects ELP1 function (PMID: 11179008, 11179021, 22190446, 23515154). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 13, 2015	- -
not provided, no classification provided	literature only	SNPedia	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 21, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2022	Functional studies in a mouse model show that c.2204+6 T>C causes alternative splicing in specific tissues and results in the skipping of exon 20 in the brain and other neuronal tissue (Bochner et al., 2013); This variant is associated with the following publications: (PMID: 17206408, 27175728, 21821670, 23515154, 22190446, 21228398, 11179021, 16964593, 12687659, 12831599, 27065010, 22975760, 23159879, 11179008, 28404519, 30609409, 29289840, 28592461, 29762696, 16032383) -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 09, 2022

The c.2204+6T>C intronic alteration consists of a T to C substitution 6 nucleotides after exon 20 (coding exon 19) of the IKBKAP gene. This alteration is also designated as c.2507+6T>C or IVS20+6T>C in the published literature. Based on data from gnomAD, the C allele has an overall frequency of 0.062% (174/282646) total alleles studied. The highest observed frequency was 1.341% (139/10364) of Ashkenazi Jewish alleles. This alteration has been reported in the homozygous state in multiple unrelated individuals with familial dysautonomia (FD) and is reported to be the most common pathogenic alteration associated with this condition (Slaugenhaupt, 2001; Anderson, 2001; Boone, 2012). This nucleotide position is well conserved in available vertebrate species. Skipping of exon 20, which is predicted to result in a frameshift, was detected in brain tissue from an individual affected with FD as well as in fibroblasts derived from multiple FD patients (Slaugenhaupt, 2001; Boone, 2012; Bruun, 2018; Ibrahim, 2007). Based on the available evidence, this alteration is classified as pathogenic. -

Medulloblastoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Oct 16, 2023

The ELP1 c.2204+6T>C intronic change results in a T to C substitution at the +6 position of intron 20 of the ELP1 gene. Algorithms that predict the impact of sequence changes on splicing indicate no significant impact on splicing. However, several studies have demonstrated tissue-specific skipping of exon 20 (PMID: 11179008, 11179021, 29762696). Skipping of exon 20 is predicted to cause premature protein truncation or absence of protein due to nonsense-mediated decay. This variant has been reported in the homozygous and compound heterozygous state in individuals with familial dysautonomia (PMID: 11179021). This variant has a frequency of 1.34% in the Ashkenazi Jewish population in gnomAD v2.1.1 (https://gnomad.broadinstitute.org) and is considered to be an Ashkenazi Jewish founder mutation. In summary, this variant meets criteria to be classified as pathogenic. -

Charcot-Marie-Tooth disease Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Inherited Neuropathy Consortium

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	21
DANN	Benign	0.90
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.66
dbscSNV1_RF	Pathogenic	0.85
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs111033171; hg19: chr9-111662096;