rs397516662

chrX-69957087-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_001399.5(EDA):c.457C>T(p.Arg153Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,638 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R153H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: EDA NM_001399.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 2.93

Genes affected

EDA (HGNC:3157): (ectodysplasin A) The protein encoded by this gene is a type II membrane protein that can be cleaved by furin to produce a secreted form. The encoded protein, which belongs to the tumor necrosis factor family, acts as a homotrimer and may be involved in cell-cell signaling during the development of ectodermal organs. Defects in this gene are a cause of ectodermal dysplasia, anhidrotic, which is also known as X-linked hypohidrotic ectodermal dysplasia. Several transcript variants encoding many different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 3 uncertain in NM_001399.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.883
• PP5: Variant X-69957087-C-T is Pathogenic according to our data. Variant chrX-69957087-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 44193.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-69957087-C-T is described in Lovd as [Pathogenic]. Variant chrX-69957087-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EDA	NM_001399.5	c.457C>T	p.Arg153Cys	missense_variant	2/8	ENST00000374552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDA	ENST00000374552.9	c.457C>T	p.Arg153Cys	missense_variant	2/8	1	NM_001399.5	P4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097638 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 363006

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

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: 0.0000217

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypohidrotic X-linked ectodermal dysplasia Pathogenic:6

Pathogenic, no assertion criteria provided	clinical testing	Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	Sep 18, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 12, 2014	The Arg153Cys variant in EDA has been reported in at least 7 individuals with X- linked hypohidrotic ectodermal dysplasia (Schneider 2001, He 2013, Clauss 2010, Schneider 2011, LMM unpublished data) and was absent from large population studi es. Functional studies have shown that the Arg153Cys variant impacts normal prot ein function (Chen 2001). This variant is located within a critical cleavage reg ion and several other pathogenic variants in the EDA gene are also found within this region. In summary, this variant meets our criteria to be classified as pat hogenic (http://pcpgm.partners.org/LMM). -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 18, 2019	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Nov 05, 2021	PS3, PM1, PM2, PP3, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 24, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 153 of the EDA protein (p.Arg153Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ectodermal dysplasia (PMID: 11279189, 20236127, 21357618, 21457804, 22875504, 24312213). ClinVar contains an entry for this variant (Variation ID: 44193). 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 EDA protein function. Experimental studies have shown that this missense change affects EDA function (PMID: 11279189, 11416205). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 11279189 , 11416205). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.57; 3Cnet: 0.87). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 11279189 , 20236127 , 21357618 , 21457804 , 22875504 , 24312213). A different missense change at the same codon (p.Arg153His) has been reported to be associated with EDA-related disorder (PMID: 24724966). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 15, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 08, 2016	- -

Anhidrotic ectodermal dysplasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 17, 2023

Variant summary: EDA c.457C>T (p.Arg153Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 182427 control chromosomes (gnomAD). c.457C>T has been reported in the literature in multiple individuals affected with Hypohidrotic Ectodermal Dysplasia (e.g. Schneider_2001, Burger_2014, Wolfhart_2016, Martinez-Romero_2019), and at least one case was reported as having a de novo origin. These data indicate that the variant is very likely to be associated with disease. At least two publications reports experimental evidence evaluating an impact on protein function (Schneider_2001, Chen_2001), finding that the variant interferes with proteolytic processing. The following publications have been ascertained in the context of this evaluation (PMID: 11279189, 11416205, 24715423, 27305980, 31796081). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
Cadd	Benign	23
Dann	Uncertain	1.0
FATHMM_MKL	Benign	0.64	D
LIST_S2	Uncertain	0.94	D;D;D;D;D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D
MetaSVM	Uncertain	-0.10	T
MutationAssessor	Benign	0.55	N;N;N;.;.
MutationTaster	Benign	0.89	D;D;D
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-2.1	N;N;N;N;.
REVEL	Uncertain	0.57
Sift	Uncertain	0.0050	D;.;.;D;.
Sift4G	Uncertain	0.051	T;T;T;D;D
Polyphen		0.91	P;P;P;.;.
Vest4		0.48
MutPred		0.79		Loss of MoRF binding (P = 0.0423);Loss of MoRF binding (P = 0.0423);Loss of MoRF binding (P = 0.0423);.;.;
MVP		1.0
MPC		1.1
ClinPred		0.73	D
GERP RS		4.1
Varity_R		0.62
gMVP		0.87

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs397516662; hg19: chrX-69176937; COSMIC: COSV104424050;