chrX-70027888-CCCTCCAGGACCCCCAGGA-C

Variant names:

• chrX-70027888-CCCTCCAGGACCCCCAGGA-C
• rs397516668
• NM_001399.5:c.572_589delCAGGACCTCCAGGACCCC

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM4 PP3 PP5_Very_Strong

The NM_001399.5(EDA):​c.572_589delCAGGACCTCCAGGACCCC​(p.Pro191_Pro196del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000219 in 914,618 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.0000022 (0 hom. 0 hem.)
• Consequence: EDA NM_001399.5 disruptive_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10 U:1
• Conservation: PhyloP100: 8.96
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• tooth agenesis, selective, X-linked, 1

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• X-linked hypohidrotic ectodermal dysplasia

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• tooth agenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001399.5.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant X-70027888-CCCTCCAGGACCCCCAGGA-C is Pathogenic according to our data. Variant chrX-70027888-CCCTCCAGGACCCCCAGGA-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 44200.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDA	NM_001399.5	c.572_589delCAGGACCTCCAGGACCCC	p.Pro191_Pro196del	disruptive_inframe_deletion	Exon 4 of 8	ENST00000374552.9	NP_001390.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EDA	ENST00000374552.9	c.572_589delCAGGACCTCCAGGACCCC	p.Pro191_Pro196del	disruptive_inframe_deletion	Exon 4 of 8	1	NM_001399.5	ENSP00000363680.4

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome AF: 0.00000219 AC: 2 AN: 914618 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 255632

African (AFR) AF: 0.00 AC: 0 AN: 22242

American (AMR) AF: 0.00 AC: 0 AN: 29582

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17911

East Asian (EAS) AF: 0.00 AC: 0 AN: 27338

South Asian (SAS) AF: 0.0000211 AC: 1 AN: 47317

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38257

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3746

European-Non Finnish (NFE) AF: 0.00000145 AC: 1 AN: 688292

Other (OTH) AF: 0.00 AC: 0 AN: 39933

GnomAD4 genome Cov.: 21

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypohidrotic X-linked ectodermal dysplasia Pathogenic:5 Uncertain:1

Feb 08, 2022

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: EDA c.572_589del18 (p.Pro191_Pro196del) results in an in-frame deletion that is predicted to remove 6 amino acids from the encoded protein. The variant was absent in 126835 control chromosomes (gnomAD). c.572_589del18 has been reported in the literature in multiple individuals/families affected with Hypohidrotic X-Linked Ectodermal Dysplasia (e.g. Bayes_1998, Schneider_2001, Martinez-Romero_2019, Wohlfart_2020). These data indicate that the variant is very likely to be associated with disease. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Apr 10, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Pro191_Pro196del (EDA) has not been reported in one individual with X-linked anhidrotic ectodermal dysplasia (Bayes 1998). This variant results in an in-fra me deletion of 6 amino acids from the conserved Gly-X-Y repeats of the collagen subdomain of the EDA protein. Several adjacent and overlapping in-frame deletion s have been identified in patients with clinical features of X-linked hypohidrot ic ectodermal dysplasia (Bayes 1998, Cluzeau 2011, LMM unpublished data). In sum mary, this variant meets our criteria to be classified as pathogenic. -

Mar 25, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Jan 08, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PS4,PM1,PM4,PS2_SUP,PM2_SUP -

Oct 21, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.572_589del, results in the deletion of 6 amino acid(s) of the EDA protein (p.Pro191_Pro196del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with hypohidrotic ectodermal dysplasia (PMID: 9736768, 11279189, 27305980). In at least one individual the variant was observed to be de novo. This variant is also known as 801/814del18. ClinVar contains an entry for this variant (Variation ID: 44200). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic. -

EDA-related disorder Pathogenic:2

Aug 29, 2024

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2, PM4, PM6 -

Jan 26, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The EDA c.572_589del18 variant is predicted to result in an in-frame deletion (p.Pro191_Pro196del). This variant is also a deletion in the collagen triple helix repeat domain of the EDA protein. This variant has been reported in patients affected with ectodermal dysplasia (Bayés et al. 1998. PubMed ID: 9736768; Wohlfart et al. 2016. PubMed ID: 27305980). Several similar deletions have also been reported to be pathogenic (Cluzeau et al. 2011. PubMed: 20979233; Schneider et al. 2011. PubMed: 21357618). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

not provided Pathogenic:2

Mar 19, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports a deleterious effect on protein structure/function; In-frame deletion of 6 amino acid(s) in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26345974, 20979233, 11279189, 31924237, 31796081, 30394555, 27305980, 9736768, 37525042) -

May 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Tooth agenesis, selective, X-linked, 1 Pathogenic:1

Feb 18, 2024

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Inframe deletion located in a nonrepeat region: predicted to change the length of the protein and disrupt normal protein function. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000044200 /PMID: 9736768 /3billion dataset). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.0
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs397516668; hg19: chrX-69247738;