rs876657686

chrX-70027978-ACCTGGTCCTCCAGGTCCT-A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PM4 PP3 PP5_Very_Strong

The NM_001399.5(EDA):c.659_676del(p.Pro220_Pro225del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 21)
• Consequence: EDA NM_001399.5 inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 9.32

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 15 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_001399.5
• PM2: Very rare variant in population databases, with high coverage
• 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-70027978-ACCTGGTCCTCCAGGTCCT-A is Pathogenic according to our data. Variant chrX-70027978-ACCTGGTCCTCCAGGTCCT-A is described in ClinVar as [Pathogenic]. Clinvar id is 228338.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-70027978-ACCTGGTCCTCCAGGTCCT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EDA	NM_001399.5	c.659_676del	p.Pro220_Pro225del	inframe_deletion	4/8	ENST00000374552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDA	ENST00000374552.9	c.659_676del	p.Pro220_Pro225del	inframe_deletion	4/8	1	NM_001399.5	P4

Frequencies

GnomAD3 genomes Cov.: 21

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 21

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypohidrotic X-linked ectodermal dysplasia Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 22, 2015	The p.Pro220_Pro225del variant in EDA has been reported in 4 individuals (3 mal es, 1 female) with clinical features of XLHED (Bayes 1998, Schneider 2011, Zhang 2011). This variant results in an in-frame deletion of 18 amino acids from the conserved Gly-X-Y repeat region of the collagen subdomain of the EDA protein. Se veral adjacent in-frame and frameshift deletions have also been identified in pa tients with clinical features of XLHED (Bayes 1998, Cluzeau 2011, Zhang 2011, LM M unpublished data), indicating that this region is intolerant to these types of variation. In summary, this variant meets our criteria to be classified as path ogenic for hypohidrotic ectodermal dysplasia in an X-linked manner. -
Pathogenic, criteria provided, single submitter	research	Medical Molecular Genetics Department, National Research Center	Feb 14, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 03, 2023	This variant, c.659_676del, results in the deletion of 6 amino acid(s) of the EDA protein (p.Pro220_Pro225del), 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 individuals with ectodermal dysplasia (PMID: 9736768, 21357618, 27305980). ClinVar contains an entry for this variant (Variation ID: 228338). This variant disrupts a region of the EDA protein in which other variant(s) (p.Pro220Leu) have been determined to be pathogenic (PMID: 25846883). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 30, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 04, 2022	In-frame deletion of 6 amino acids in a non-repeat region predicted to critically alter the protein; Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27305980, 25140498, 9736768, 20979233, 30394555, 24279917, 34573371, 21357618, 23553579, 24715423, 21457804, 26345974, 31924237) -

Anhidrotic ectodermal dysplasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

May 22, 2023

Variant summary: EDA c.659_676del18 (p.Pro220_Pro225del) results in an in-frame deletion that is predicted to remove 6 amino acids from the encoded protein. The variant was absent in 146336 control chromosomes (gnomAD). c.659_676del18 has been reported in the literature in in both male and female individuals affected with Hypohidrotic Ectodermal Dysplasia, including a de novo occurrence (e.g. Bayes_1998, Schneider_2011, Cluzeau_2011, Ahmed_2021). These data indicate that the variant is 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: 9736768, 21357618, 20979233, 34573371). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs876657686; hg19: chrX-69247828;