Submissions for variant NM_003640.5(ELP1):c.2204+6T>C (rs111033171)

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000058928	SCV000218960	pathogenic	not provided	2019-12-31	criteria provided, single submitter	clinical testing	This sequence change falls in intron 20 of the ELP1 mRNA. It does not directly change the encoded amino acid sequence of the ELP1 protein. This variant is present in population databases (rs111033171, ExAC 0.1%). This variant is a common pathogenic sequence change among individuals of Ashkenazi Jewish ancestry (PMID: 11179021, 11179008, 12116234). The carrier frequency of this is 1/32 (3.2%) in individuals of Ashkenazi Jewish ancestry, accounting for >99% of familial dysautonomia (FD) cases among the Ashkenazi Jewish population (PMID: 12116234, 20301359). ClinVar contains an entry for this variant (Variation ID: 6085). Experimental studies have shown that this variant affects mRNA splicing causing tissue-specific skipping of exon 20, leading to changes in neuronal gene expression and development (PMID: 11179008, 11179021, 22190446, 23515154). For these reasons, this variant has been classified as Pathogenic.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000058928	SCV000227662	pathogenic	not provided	2015-04-13	criteria provided, single submitter	clinical testing
GeneDx	RCV000058928	SCV000589336	pathogenic	not provided	2019-01-21	criteria provided, single submitter	clinical testing	The c.2204+6 T>C pathogenic splice site variant in the IKBKAP gene has been previously reported as a founder mutation in the Ashkenazi Jewish population with a reported carrier frequency of 1 in 36 individuals (Slaugenhaupt et al., 2001). 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). Therefore, c.2204+6 T>C is interpreted to be a pathogenic variant.
Integrated Genetics/Laboratory Corporation of America	RCV000006458	SCV000698209	pathogenic	Familial dysautonomia	2017-08-21	criteria provided, single submitter	clinical testing	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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine	RCV000006458	SCV000712784	pathogenic	Familial dysautonomia	2019-07-25	criteria provided, single submitter	clinical testing	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.
Fulgent Genetics,Fulgent Genetics	RCV000006458	SCV000894464	pathogenic	Familial dysautonomia	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000006458	SCV000916278	pathogenic	Familial dysautonomia	2018-11-30	criteria provided, single submitter	clinical testing	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.
Myriad Women's Health, Inc.	RCV000006458	SCV001194222	pathogenic	Familial dysautonomia	2019-10-18	criteria provided, single submitter	clinical testing	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.
OMIM	RCV000006458	SCV000026641	pathogenic	Familial dysautonomia	2007-01-01	no assertion criteria provided	literature only
SNPedia	RCV000058928	SCV000090449	not provided	not provided		no assertion provided	not provided
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen	RCV000006458	SCV000734628	pathogenic	Familial dysautonomia		no assertion criteria provided	clinical testing
Inherited Neuropathy Consortium	RCV000789357	SCV000928711	uncertain significance	Charcot-Marie-Tooth disease		no assertion criteria provided	literature only
Reproductive Health Research and Development,BGI Genomics	RCV000006458	SCV001142401	pathogenic	Familial dysautonomia	2020-01-06	no assertion criteria provided	curation	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.
Natera, Inc.	RCV000006458	SCV001457910	pathogenic	Familial dysautonomia	2020-09-16	no assertion criteria provided	clinical testing