rs121908453

Positions:

• chr2-108896995-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_022336.4(EDAR):​c.1259G>A​(p.Arg420Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R420W) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EDAR NM_022336.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 5.86

Genes affected

EDAR (HGNC:2895): (ectodysplasin A receptor) This gene encodes a member of the tumor necrosis factor receptor family. The encoded transmembrane protein is a receptor for the soluble ligand ectodysplasin A, and can activate the nuclear factor-kappaB, JNK, and caspase-independent cell death pathways. It is required for the development of hair, teeth, and other ectodermal derivatives. Mutations in this gene result in autosomal dominant and recessive forms of hypohidrotic ectodermal dysplasia. [provided by RefSeq, Jul 2008]

RANBP2 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-108896996-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.951
• PP5: Variant 2-108896995-C-T is Pathogenic according to our data. Variant chr2-108896995-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 5853.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-108896995-C-T is described in Lovd as [Pathogenic]. Variant chr2-108896995-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EDAR	NM_022336.4	c.1259G>A	p.Arg420Gln	missense_variant	12/12	ENST00000258443.7	NP_071731.1
EDAR	XM_006712204.2	c.1355G>A	p.Arg452Gln	missense_variant	11/11		XP_006712267.1
RANBP2	XM_047445367.1	c.8370+123949C>T		intron_variant			XP_047301323.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EDAR	ENST00000258443.7	c.1259G>A	p.Arg420Gln	missense_variant	12/12	1	NM_022336.4	ENSP00000258443	P1
EDAR	ENST00000376651.1	c.1355G>A	p.Arg452Gln	missense_variant	11/11	2		ENSP00000365839
EDAR	ENST00000409271.5	c.1355G>A	p.Arg452Gln	missense_variant	12/12	2		ENSP00000386371

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Oct 10, 2022	PS3, PS4, PM1, PM2, PP3 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Jan 01, 2019	- -
Pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Oct 15, 2018	This variant is interpreted as Pathogenic, for Ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PM6 => Assumed de novo, but without confirmation of paternity and maternity (https://www.ncbi.nlm.nih.gov/pubmed/16435307). PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (https://www.ncbi.nlm.nih.gov/pubmed/18231121) (https://www.ncbi.nlm.nih.gov/pubmed/10431241). PM1 => Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation (http://www.uniprot.org/uniprot/Q9UNE0). PS3 => Well-established functional studies show a deleterious effect (https://www.ncbi.nlm.nih.gov/pubmed/11035039). -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant c.1259G>Ap.Arg420Gln in EDAR gene has been reported previously in heterozygous state in multiple individuals with Ectodermal Dysplasia Zeng B, et al., 2016, Cluzeau C, et al., 2011. Experimental studies have shown that this missense change affects EDAR function Shindo M, Chaudhary PM, 2004. The variant is novel not in any individuals in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic. The amino acid Arginine at position 420 is changed to a Glutamine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by SIFT. The amino acid change p.Arg420Gln in EDAR is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 20, 2024	Published functional studies demonstrate a damaging effect: R420Q disrupts NF-kB pathway activation and turns off repression of the Lef-1/b-catenin-dependent transcriptional activity leading to abnormal ectodermal differentiation and hair follicle morphogenesis (PMID: 11035039, 15013427); Not observed in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 17943131, 18231121, 15013427, 29364747, 20301291, 11035039, 31245878, 16435307, 10431241) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 19, 2016	- -

Ectodermal dysplasia 11B, hypohidrotic/hair/tooth type, autosomal recessive Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jan 25, 2018

This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been reported in a family with autosomal dominant hypohidrotic ectodermal dysplasia [PMID: 10431241] and was shown to decrease the EDAR protein's ability to repress the Lef-1/b-catenin activity in vitro [PMID: 15013427] -

Autosomal recessive hypohidrotic ectodermal dysplasia syndrome;C3888065:Ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 08, 2023

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects EDAR function (PMID: 11035039, 15013427). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on EDAR protein function. ClinVar contains an entry for this variant (Variation ID: 5853). This missense change has been observed in individual(s) with autosomal dominant hypohidrotic ectodermal dysplasia (PMID: 10431241, 16435307, 18231121, 20979233, 23401279, 27657131). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 420 of the EDAR protein (p.Arg420Gln). -

Ectodermal dysplasia 10a, hypohidrotic/hair/tooth type, autosomal dominant Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 1999

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.62	.;D;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	.;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Uncertain	0.47	D
MutationAssessor	Benign	0.55	.;N;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.023	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.92
MutPred		0.91		.;Gain of solvent accessibility (P = 0.0374);.;
MVP		0.96
MPC		1.1
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.32
gMVP		0.99

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: rs121908453; hg19: chr2-109513451; COSMIC: COSV105860984;