rs132630312

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong

The NM_001399.5(EDA):c.463C>T(p.Arg155Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000331 in 1,209,991 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.0000018 ( 0 hom. 1 hem. )

Consequence

EDA
NM_001399.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 2.04

Variant links:

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]

EDA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.778

PP5

Variant X-69957093-C-T is Pathogenic according to our data. Variant chrX-69957093-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 11035.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-69957093-C-T is described in Lovd as [Pathogenic]. Variant chrX-69957093-C-T is described in Lovd as [Pathogenic]. Variant chrX-69957093-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDA	NM_001399.5 link	c.463C>T	p.Arg155Cys	missense_variant	Exon 2 of 8	ENST00000374552.9	NP_001390.1	Q92838-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EDA	ENST00000374552.9 link	c.463C>T	p.Arg155Cys	missense_variant	Exon 2 of 8	1	NM_001399.5	ENSP00000363680.4		Q92838-1

Frequencies

GnomAD3 genomes

AF:

0.0000178

AC:

AN:

112345

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34523

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000188

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000182

AC:

AN:

1097646

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

363020

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000331

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000119

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000178

AC:

AN:

112345

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34523

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000188

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypohidrotic X-linked ectodermal dysplasia

Pathogenic:8

Jun 11, 2021

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PS4, PM1, PM2, PM6 -

Dec 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 155 of the EDA protein (p.Arg155Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with X-linked hypohidrotic ectodermal dsyplasia (XLHED) (PMID: 9683615, 18231121, 18821982, 20486090, 22428923, 25333067, 26273176, 27054699, 27305980, 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. ClinVar contains an entry for this variant (Variation ID: 11035). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt EDA protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Jun 24, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. The following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with X-linked hypohidrotic ectodermal dysplasia 1 (MIM#305100) and selective tooth agenesis (MIM#313500). (I) 0110 - This gene is associated with X-linked disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes, 0 hemizygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (21 heterozygotes, 0 homozygotes, 13 hemizygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the consensus furin motif (PMID: 11416205). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is well-reported in the literature and has been reported in at least ten individuals with hypohidrotic ectodermal dysplasia (HED) (ClinVar; PMID: 27054699; 27305980; 26273176). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. The variant resides within a consensus furin motif and in vitro studies demonstrated that this variant impacts protein cleavage (PMID: 11416205) (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Oct 24, 2022

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PM1, PM2, PP3, PP5 -

Oct 23, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). Predicted Consequence/Location: Missense variant Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 11735257). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.80 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.98 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000043384 /PMID: 9241277 /3billion dataset). The variant has been reported to co-segregate with the disease in at least 7 similarly affected relatives/individuals in at least two unrelated families (PMID: 15607392, 23283745, 24111713, 25132132, 9241277). Different missense changes at the same codon (p.Arg145Gly, p.Arg145Trp) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012419, VCV000012426 /PMID: 12531876, 9241277). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Jun 10, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg155Cys variant in EDA has been reported in 6 affected males with X-link ed hypohidrotic ectodermal dysplasia (XLHED) and segregated with disease in 1 af fected male and 5 carrier females from 3 families (Monreal 1998, Schneider 2001, Fan 2008, Khabour 2010, Callea 2013, Zhu 2013). It was absent from large popula tion studies. Furthermore, this variant has been identified by our laboratory in 5 individuals with XLHED. This variant resides in the furin domain of EDA and i n-vitro functional studies suggest that this variant impacts protein cleavage (C hen, 2001). In summary, this variant meets our criteria to be classified as path ogenic for XLHED based upon segregation studies, absence from controls, and func tional evidence. -

Nov 12, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided

Pathogenic:3

Apr 22, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect (PMID: 11416205); Missense variants in this gene are often considered pathogenic (HGMD); Not observed in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22428923, 24033266, 11279189, 34573371, 23926003, 20486090, 18821982, 9683615, 27054699, 11378824, 28045201, 30417976, 31129666, 31924237, 34863015, 11416205) -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hypohidrotic X-linked ectodermal dysplasia;C1970757:Tooth agenesis, selective, X-linked, 1

Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.55

.;D;.;.;.

FATHMM_MKL

Benign

0.63

LIST_S2

Uncertain

0.94

D;D;D;D;D

M_CAP

Pathogenic

0.30

MetaRNN

Pathogenic

0.78

D;D;D;D;D

MetaSVM

Uncertain

-0.14

MutationAssessor

Benign

0.55

N;N;N;.;.

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.4

N;N;N;N;.

REVEL

Uncertain

0.45

Sift

Uncertain

0.0010

D;.;.;D;.

Sift4G

Benign

0.093

T;T;T;D;D

Polyphen

0.014

B;B;B;.;.

Vest4

0.58

MutPred

0.82

Loss of MoRF binding (P = 0.0275);Loss of MoRF binding (P = 0.0275);Loss of MoRF binding (P = 0.0275);.;.;

MVP

1.0

MPC

1.1

ClinPred

0.50

GERP RS

3.2

Varity_R

0.56

gMVP

0.89

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over