rs137853022

Positions:

• chr9-108900303-C-G
• chr9-108900303-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_003640.5(ELP1):​c.2087G>C​(p.Arg696Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ELP1 NM_003640.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 U:1 O:1
• Conservation: PhyloP100: 5.58

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]

ELP1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.961
• PP5: Variant 9-108900303-C-G is Pathogenic according to our data. Variant chr9-108900303-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 6086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-108900303-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ELP1	NM_003640.5	c.2087G>C	p.Arg696Pro	missense_variant	19/37	ENST00000374647.10	NP_003631.2
ELP1	NM_001318360.2	c.1745G>C	p.Arg582Pro	missense_variant	19/37		NP_001305289.1
ELP1	NM_001330749.2	c.1040G>C	p.Arg347Pro	missense_variant	17/35		NP_001317678.1
ELP1	XM_047423991.1	c.2087G>C	p.Arg696Pro	missense_variant	19/25		XP_047279947.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ELP1	ENST00000374647.10	c.2087G>C	p.Arg696Pro	missense_variant	19/37	1	NM_003640.5	ENSP00000363779.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461856 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial dysautonomia Pathogenic:4 Other:1

Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
not provided, no classification provided	literature only	GeneReviews	-	A rare variant identified in Ashkenazi Jews -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2002	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 09, 2019	NM_003640.3(IKBKAP):c.2087G>C(R696P) is classified as likely pathogenic in the context of familial dysautonomia. Sources cited for classification include the following: PMID 11179008 and 11179021. Classification of NM_003640.3(IKBKAP):c.2087G>C(R696P) is based on the following criteria: This variant 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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 13, 2021	Variant summary: IKBKAP c.2087G>C (p.Arg696Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 259280 control chromosomes (gnomAD and publication data). c.2087G>C has been reported in the literature in multiple individuals affected with Familial Dysautonomia (Slaugenhaupt_2001, Anderson_2001, Gutirrez_2017). These data indicate that the variant is very likely to be associated with disease. At least one function study reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Anderson_2001). Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=3) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 08, 2021	This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 696 of the ELP1 protein (p.Arg696Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with familial dysautonomia (PMID: 11179008, 11179021, 12116234). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 11179008, 11179021, 12116234). ClinVar contains an entry for this variant (Variation ID: 6086). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects ELP1 function (PMID: 11179021). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Familial dysautonomia;C0025149:Medulloblastoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 11, 2021

- -

Charcot-Marie-Tooth disease Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Inherited Neuropathy Consortium

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T;T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.088	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Benign	-0.44	T
MutationAssessor	Pathogenic	3.7	H;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-4.8	D;D
REVEL	Uncertain	0.54
Sift	Uncertain	0.021	D;D
Sift4G	Uncertain	0.017	D;D
Polyphen		1.0	D;.
Vest4		0.96
MutPred		0.84		Loss of MoRF binding (P = 3e-04);.;
MVP		0.76
MPC		0.50
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.91
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs137853022; hg19: chr9-111662583;