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

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Interpretation:
Pathogenic​

Review status:
criteria provided, multiple submitters, no conflicts
Submissions:
12 (Most recent: Jul 10, 2019)
Last evaluated:
Jan 21, 2019
Accession:
VCV000006085.5
Variation ID:
6085
Description:
single nucleotide variant
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NM_003640.5(ELP1):c.2204+6T>C

Allele ID
21124
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
9q31.3
Genomic location
9: 108899816 (GRCh38) GRCh38 UCSC
9: 111662096 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
LRG_251t1:c.2204+6T>C
NC_000009.12:g.108899816A>G
NC_000009.11:g.111662096A>G
... more HGVS
Protein change
-
Other names
IVS20DS, T-C, +6
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
Trans-Omics for Precision Medicine (TOPMed) 0.00047
Exome Aggregation Consortium (ExAC) 0.00065
The Genome Aggregation Database (gnomAD) 0.00035
The Genome Aggregation Database (gnomAD), exomes 0.00065
Links
ClinGen: CA284834
OMIM: 603722.0001
dbSNP: rs111033171
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Pathogenic 4 criteria provided, multiple submitters, no conflicts Jan 21, 2019 RCV000058928.4
Pathogenic 7 criteria provided, multiple submitters, no conflicts Nov 30, 2018 RCV000006458.14
Uncertain significance 1 no assertion criteria provided - RCV000789357.1
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
ELP1 - - GRCh38
GRCh37
389 427

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Pathogenic
(Aug 21, 2017)
criteria provided, single submitter
Method: clinical testing
Familial dysautonomia
Allele origin: germline
Integrated Genetics/Laboratory Corporation of America
Accession: SCV000698209.1
Submitted: (Jan 25, 2018)
Evidence details
Publications
PubMed (2)
Comment:
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 ... (more)
Pathogenic
(Jan 17, 2017)
criteria provided, single submitter
Method: clinical testing
Familial dysautonomia
(Autosomal recessive inheritance)
Allele origin: germline
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine
Accession: SCV000712784.1
Submitted: (Mar 21, 2019)
Evidence details
Publications
PubMed (8)
Comment:
The c.2204+6T>C variant (NM_003640.3 c.2204+6T>C) in IKBKAP has been reported in several individuals with familial dysautonomia and is a founder mutation in the Ashkenazi Jewish ... (more)
Pathogenic
(Oct 31, 2018)
criteria provided, single submitter
Method: clinical testing
Familial dysautonomia
Allele origin: unknown
Fulgent Genetics,Fulgent Genetics
Accession: SCV000894464.1
Submitted: (Nov 14, 2018)
Evidence details
Publications
PubMed (1)
DOI: 10.1038/gim.2015.30
Pathogenic
(Nov 30, 2018)
criteria provided, single submitter
Method: clinical testing
Familial dysautonomia
Allele origin: germline
Illumina Clinical Services Laboratory,Illumina
Accession: SCV000916278.1
Submitted: (Feb 01, 2019)
Evidence details
Publications
PubMed (5)
Comment:
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 ... (more)
Pathogenic
(Nov 24, 2015)
criteria provided, single submitter
Method: clinical testing
Familial dysautonomia
Allele origin: unknown
Counsyl
Accession: SCV000485216.1
Submitted: (Nov 23, 2016)
Evidence details
Pathogenic
(Apr 13, 2015)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics
Accession: SCV000227662.5
Submitted: (Sep 19, 2018)
Evidence details
Publications
PubMed (2)
Other databases
http://www.egl-eurofins.com/em...
Pathogenic
(Jan 21, 2019)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV000589336.3
Submitted: (Jan 29, 2019)
Evidence details
Comment:
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 ... (more)
Pathogenic
(Dec 11, 2018)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
Invitae
Accession: SCV000218960.8
Submitted: (Mar 28, 2019)
Evidence details
Publications
PubMed (5)
Comment:
This sequence change falls in intron 20 of the IKBKAP mRNA. It does not directly change the encoded amino acid sequence of the IKBKAP protein. ... (more)
Pathogenic
(-)
no assertion criteria provided
Method: clinical testing
Familial dysautonomia
Allele origin: germline
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV000734628.1
Submitted: (Apr 04, 2018)
Evidence details
Uncertain significance
(-)
no assertion criteria provided
Method: literature only
Charcot-Marie-Tooth disease
Allele origin: germline
Inherited Neuropathy Consortium
Accession: SCV000928711.1
Submitted: (Jul 10, 2019)
Evidence details
Publications
PubMed (1)
Pathogenic
(Jan 01, 2007)
no assertion criteria provided
Method: literature only
DYSAUTONOMIA, FAMILIAL
Allele origin: germline
OMIM
Accession: SCV000026641.1
Submitted: (Dec 30, 2010)
Evidence details
Publications
PubMed (3)
not provided
(-)
no assertion provided
Method: not provided
not provided
Allele origin: germline
SNPedia
Accession: SCV000090449.1
Submitted: (Apr 26, 2011)
Evidence details

Citations for this variant

Title Author Journal Year Link
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. Nykamp K Genetics in medicine : official journal of the American College of Medical Genetics 2017 PMID: 28492532
Analysis of 589,306 genomes identifies individuals resilient to severe Mendelian childhood diseases. Chen R Nature biotechnology 2016 PMID: 27065010
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Richards S Genetics in medicine : official journal of the American College of Medical Genetics 2015 PMID: 25741868
Familial Dysautonomia Shohat M - 2014 PMID: 20301359
Phosphatidylserine increases IKBKAP levels in a humanized knock-in IKBKAP mouse model. Bochner R Human molecular genetics 2013 PMID: 23515154
Genome-wide analysis of familial dysautonomia and kinetin target genes with patient olfactory ecto-mesenchymal stem cells. Boone N Human mutation 2012 PMID: 22190446
Weak definition of IKBKAP exon 20 leads to aberrant splicing in familial dysautonomia. Ibrahim EC Human mutation 2007 PMID: 16964593
Familial dysautonomia: detection of the IKBKAP IVS20(+6T --> C) and R696P mutations and frequencies among Ashkenazi Jews. Dong J American journal of medical genetics 2002 PMID: 12116234
Familial dysautonomia is caused by mutations of the IKAP gene. Anderson SL American journal of human genetics 2001 PMID: 11179021
Tissue-specific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia. Slaugenhaupt SA American journal of human genetics 2001 PMID: 11179008
Statistical features of human exons and their flanking regions. Zhang MQ Human molecular genetics 1998 PMID: 9536098
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ELP1 - - - -
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=IKBKAP - - - -

Record last updated Oct 27, 2019