chrX-70027972-GGGACCACCTGGTCCTCCAGGTCCTCCTGGTCCTCAA-G

Position:

• chrX-70027972-GGGACCACCTGGTCCTCCAGGTCCTCCTGGTCCTCAA-G

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.648_683del​(p.Pro219_Gly230del) 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 21)
• Consequence: EDA NM_001399.5 inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• 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-70027972-GGGACCACCTGGTCCTCCAGGTCCTCCTGGTCCTCAA-G is Pathogenic according to our data. Variant chrX-70027972-GGGACCACCTGGTCCTCCAGGTCCTCCTGGTCCTCAA-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 228337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EDA	NM_001399.5	c.648_683del	p.Pro219_Gly230del	inframe_deletion	4/8	ENST00000374552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDA	ENST00000374552.9	c.648_683del	p.Pro219_Gly230del	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/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypohidrotic X-linked ectodermal dysplasia Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 04, 2015	The p.Pro219_Gly230del variant in EDA has not been previously reported in indivi duals with XLHED. However, this variant results in an in-frame deletion of 11 am ino acids from the conserved Gly-X-Y repeat region of the collagen subdomain of the EDA protein. Several adjacent and overlapping in-frame and frameshift deleti ons have been identified in patients with clinical features of XLHED (Bayes 1998 , Cluzeau 2011, Zhang 2011, LMM unpublished data), indicating that this region i s intolerant to these types of variation. In summary, this variant meets our cri teria to be classified as pathogenic for hypohidrotic ectodermal dysplasia in an X-linked manner. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 07, 2023	This variant, c.648_683del, results in the deletion of 12 amino acid(s) of the EDA protein (p.Pro219_Gly230del), 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 ectodermal dysplasia (PMID: 29444360). ClinVar contains an entry for this variant (Variation ID: 228337). This variant disrupts a region of the EDA protein in which other variant(s) (p.Pro220_Pro225del) have been determined to be pathogenic (PMID: 9736768, 21357618, 27305980). 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	GeneDx	Oct 17, 2017	The c.648_683del36 deletion has not been reported previously in association with X-linked hypohidrotic ectodermal dysplasia (HED) to our knowledge. This in-frame deletion results in the deletion of 12 amino acids in the collagen-like domain of the ectodysplasin protein, beginning at Proline 219 and ending at Glycine 230, denoted p.Pro219_Gly230del. This variant is not expected to result in protein truncation or nonsense-mediated mRNA decay. An in-frame deletion beginning from the same position, c.648_665del18, has been published in the Human Gene Mutation Database in association with hypohidrotic ectodermal dysplasia. Therefore, the c.648_683del36 deletion is interpreted as a pathogenic variant. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 04, 2020	- -

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: rs876657685; hg19: chrX-69247822;