NM_003640.5(ELP1):c.2204+6T>C AND not provided

Germline classification:: Pathogenic (6 submissions)
Last evaluated:: Jan 29, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000058928.25

Allele description [Variation Report for NM_003640.5(ELP1):c.2204+6T>C]

NM_003640.5(ELP1):c.2204+6T>C

Gene:

ELP1:elongator acetyltransferase complex subunit 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

9q31.3

Genomic location:

Preferred name:

NM_003640.5(ELP1):c.2204+6T>C

HGVS:

NC_000009.12:g.108899816A>G
NG_008788.1:g.39513T>C
NM_001318360.2:c.1862+6T>C
NM_001330749.2:c.1157+6T>C
NM_003640.4(ELP1):c.2204+6T>C
NM_003640.5:c.2204+6T>CMANE SELECT
LRG_251t1:c.2204+6T>C
LRG_251:g.39513T>C
NC_000009.11:g.111662096A>G
NM_003640.3:c.2204+6T>C
NM_003640.4(ELP1):c.2204+6T>C
NM_003640.4:c.2204+6T>C
c.2204+6T>C (p.?)

Nucleotide change:

IVS20DS, T-C, +6

Links:

OMIM: 603722.0001; dbSNP: rs111033171

NCBI 1000 Genomes Browser:

rs111033171

Molecular consequence:

NM_001318360.2:c.1862+6T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001330749.2:c.1157+6T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_003640.5:c.2204+6T>C - intron variant - [Sequence Ontology: SO:0001627]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000090449	SNPedia	no classification provided	not provided	germline	not provided
SCV000218960	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 29, 2024)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 12116234, 20301359, 11179008, 11179021, 22190446, 23515154, 17576681, 9536098, 28492532
SCV000227662	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Pathogenic (Apr 13, 2015)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 11179008, 16964593 Citation Link,
SCV000589336	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jul 5, 2022)	germline	clinical testing	Citation Link,
SCV001714303	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 21, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001925450	Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	15	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Familial dysautonomia: detection of the IKBKAP IVS20(+6T --> C) and R696P mutations and frequencies among Ashkenazi Jews.

Dong J, Edelmann L, Bajwa AM, Kornreich R, Desnick RJ.

Am J Med Genet. 2002 Jul 1;110(3):253-7.

PubMed [citation]

PMID:: 12116234

Familial Dysautonomia.

Bar-Aluma BE.

2003 Jan 21 [updated 2021 Nov 4]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(®) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.

PubMed [citation]

PMID:: 20301359

See all PubMed Citations (11)

Details of each submission

From SNPedia, SCV000090449.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	not provided	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000218960.13

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Eurofins Ntd Llc (ga), SCV000227662.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	10	not provided	not provided	clinical testing	PubMed (2)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		10	not provided	not provided	not provided

From GeneDx, SCV000589336.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Mayo Clinic Laboratories, Mayo Clinic, SCV001714303.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	5	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		5	not provided	not provided	not provided

From Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus, SCV001925450.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 26, 2024

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