rs397516677

Positions:

• chrX-70033475-G-A

Variant summary

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

The NM_001399.5(EDA):​c.871G>A​(p.Gly291Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,098,115 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. G291W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 23)
  • 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:5
• Conservation: PhyloP100: 9.33

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 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 chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant X-70033475-G-A is Pathogenic according to our data. Variant chrX-70033475-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 44211.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-70033475-G-A is described in Lovd as [Likely_pathogenic]. Variant chrX-70033475-G-A is described in Lovd as [Pathogenic]. Variant chrX-70033475-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.871G>A	p.Gly291Arg	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.871G>A	p.Gly291Arg	missense_variant	7/8	1	NM_001399.5	ENSP00000363680	P4
EDA	ENST00000374553.6	c.871G>A	p.Gly291Arg	missense_variant	7/8	1		ENSP00000363681	A1
EDA	ENST00000524573.5	c.862G>A	p.Gly288Arg	missense_variant	7/8	1		ENSP00000432585	A1
EDA	ENST00000616899.1	c.475G>A	p.Gly159Arg	missense_variant	6/7	5		ENSP00000481963

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1098115 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 363471

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: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypohidrotic X-linked ectodermal dysplasia Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 24, 2022	For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 291 of the EDA protein (p.Gly291Arg). This missense change has been observed in individual(s) with hypohidrotic/anhidrotic ectodermal dysplasia (PMID: 9736768, 20979233, 21357618, 22032522, 23553579). This variant is also known as c.1113G>A. ClinVar contains an entry for this variant (Variation ID: 44211). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 17, 2011	The Gly291Arg variant in EDA has been reported in at least 11 individuals with X -linked hypohidrotic ectodermal dysplasia. It was reported as de novo in two of these individuals and was absent from over 300 control chromosomes (Bayes 1998, Cluzeau 2011, Schneider 2001, Schneider 2011, Sekiguchi 2005, LMM unpublished d ata). In summary, this variant meets our criteria to be classified as pathogeni c. -
Pathogenic, criteria provided, single submitter	research	Medical Molecular Genetics Department, National Research Center	Feb 13, 2021	- -

Anhidrotic ectodermal dysplasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Oct 18, 2023

Variant summary: EDA c.871G>A (p.Gly291Arg) results in a non-conservative amino acid change located in a critical position within the Tumour necrosis factor domain (IPR006052) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183325 control chromosomes. c.871G>A has been reported in the literature in multiple individuals affected with Hypohidrotic Ectodermal Dysplasia (example, Bayes_1998, Sekiguchi_2005, Zeng_2015, Kang_2022, Park_2019). 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: 15663448, 9736768, 26411740, 36071541, 31129666, 11279189, 18231121). Three 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. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 05, 2021

Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); Identified in multiple patients with X-linked hypohidrotic ectodermal dysplasia referred for genetic testing at GeneDx and in published literature (Schneider et al., 2001; Bayes et al., 1998; Cluzeau et al., 2011); This variant is associated with the following publications: (PMID: 9736768, 22032522, 23553579, 18231121, 21357618, 24033266, 20979233, 19278982, 11279189, 31129666) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.67	D
BayesDel_noAF	Pathogenic	0.72
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	.;D;.;.
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.3	M;M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.9	D;D;D;.
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0060	D;.;.;.
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.99
MutPred		0.94		Gain of solvent accessibility (P = 0.0674);Gain of solvent accessibility (P = 0.0674);.;.;
MVP		1.0
MPC		2.0
ClinPred		1.0	D
GERP RS		5.5
Varity_R		1.0
gMVP		0.99

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs397516677; hg19: chrX-69253325;