rs876657641

Positions:

• chrX-70033470-G-A
• chrX-70033470-G-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM5 PP3_Moderate PP5_Very_Strong

The ENST00000374552.9(EDA):​c.866G>A​(p.Arg289His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00001 in 1,098,037 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. 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. R289P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000010 (0 hom. 5 hem.)
• Consequence: EDA ENST00000374552.9 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 9.36

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 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in ENST00000374552.9
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-70033469-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 253054.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.889
• PP5: Variant X-70033470-G-A is Pathogenic according to our data. Variant chrX-70033470-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 228257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-70033470-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EDA	NM_001399.5	c.866G>A	p.Arg289His	missense_variant	7/8	ENST00000374552.9	NP_001390.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EDA	ENST00000374552.9	c.866G>A	p.Arg289His	missense_variant	7/8	1	NM_001399.5	ENSP00000363680	P4
EDA	ENST00000374553.6	c.866G>A	p.Arg289His	missense_variant	7/8	1		ENSP00000363681	A1
EDA	ENST00000524573.5	c.857G>A	p.Arg286His	missense_variant	7/8	1		ENSP00000432585	A1
EDA	ENST00000616899.1	c.470G>A	p.Arg157His	missense_variant	6/7	5		ENSP00000481963

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.0000100 AC: 11 AN: 1098037 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 5 AN XY: 363395

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: 0.0000131

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000378

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypohidrotic X-linked ectodermal dysplasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 09, 2023

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg289 amino acid residue in EDA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19278982, 24487376, 27144394). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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) performed at Invitae indicates that this missense variant is expected to disrupt EDA protein function. ClinVar contains an entry for this variant (Variation ID: 228257). This missense change has been observed in individual(s) with ectodermal dysplasia (PMID: 26753551; Invitae). 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 histidine, which is basic and polar, at codon 289 of the EDA protein (p.Arg289His). -

Anhidrotic ectodermal dysplasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jun 20, 2023

Variant summary: EDA c.866G>A (p.Arg289His) results in a non-conservative amino acid change located in the Tumor necrosis factor domain (IPR006052) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183333 control chromosomes in gnomAD. c.866G>A has been reported in the literature in multiple hemizygous individuals affected with features of Hypohidrotic Ectodermal Dysplasia (with dental anomalies being the main symptoms) and has been observed to co-segregate with disease within families (example: Ruiz-Heiland_2016, Andreoni_2021, Zhang _2021, Biedziak_2022). Some female carriers have been reported with mild features of tooth agenesis, while others were unaffected (example: Ruiz-Heiland_2016, Andreoni_2021, Zhang _2021). Additionally, at least one variant at the Arg289 residue has been reported as associated with disease (p.Arg289Cys), suggesting that this codon is functionally important. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33205897, 36294409, 26753551, 33943035). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and all submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Biotechnology Lab, Dept of Biomolecular Sciences, University of Urbino

Jun 01, 2020

The Arg289His variant in EDA has been reported in one Italian family with X-linked dominant tooth agenesis, segregated with the disease in affected relatives (present study), and was absent from large population studies. Additionally, the same variant causes X-linked recessive hypohidrotic ectodermal dysplasia in hemizygous males within the same family. Furthermore, this variant has been described to segregate with non-syndromic oligodontia and ectodermal dysplasia in families (PMID: 26753551, Invitae). Two other missense variants affecting the same amino acidic residue Arg289 (c.865C>T p.Arg289Cys, c.866G>T p.Arg289Leu), but causing different amino acid substitutions, has been reported to be pathogenic and associated to non-syndromic oligodontia (PMID: 19278982, 24487376). In summary, the Arg289His variant meets our criteria to be classified as pathogenic. -

Partial congenital absence of teeth Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 11, 2015

The p.Arg289His variant in EDA has been reported in one individual with non-synd romic oligodontia and segregated with disease in one sibling (Heiland 2014, conf erence abstract). The variant was absent from large population studies. Computat ional prediction tools and conservation analysis suggest that the p.Arg289His va riant may impact the protein. In additon, two other missense variants at the sam e amino acid position (p.Arg289Cys, p.Arg289Leu) have been reported in individua ls with non-syndromic oligodontia (Song 2009, Lee 2014), suggesting that variati on at this position is not tolerated. In summary, although additional studies ar e required to fully establish its clinical significance, the p.Arg289His variant is likely pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2024

EDA: PP1:Strong, PM1, PM2, PM5, PP3, PP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	.;D;.;.
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.88	D;D;D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.89	D;D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Benign	1.5	L;L;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.83	N;N;N;.
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D;.;.;.
Sift4G	Benign	0.18	T;T;T;T
Polyphen		1.0	D;D;D;.
Vest4		0.84
MutPred		0.63		Loss of methylation at R289 (P = 0.0444);Loss of methylation at R289 (P = 0.0444);.;.;
MVP		0.99
MPC		1.2
ClinPred		0.95	D
GERP RS		5.5
Varity_R		0.98
gMVP		0.91

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs876657641; hg19: chrX-69253320; COSMIC: COSV100999888; COSMIC: COSV100999888;