rs397516668

chrX-70027888-CCCTCCAGGACCCCCAGGA-CchrX-70027888-CCCTCCAGGACCCCCAGGA-CCCTCCAGGACCCCCAGGACCTCCAGGACCCCCAGGA

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM4 PP3 PP5

The NM_001399.5(EDA):c.572_589del(p.Pro191_Pro196del) variant causes a 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.0000022 (0 hom. 0 hem.)
• Consequence: EDA NM_001399.5 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8 U:1
• Conservation: PhyloP100: 8.96

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a domain Collagen-like (size 49) in uniprot entity EDA_HUMAN there are 38 pathogenic changes around while only 0 benign (100%) 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-70027888-CCCTCCAGGACCCCCAGGA-C is Pathogenic according to our data. Variant chrX-70027888-CCCTCCAGGACCCCCAGGA-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44200.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=7, Uncertain_significance=1}. Variant chrX-70027888-CCCTCCAGGACCCCCAGGA-C is described in Lovd as [Pathogenic]. Variant chrX-70027888-CCCTCCAGGACCCCCAGGA-C is described in Lovd as [Pathogenic]. Variant chrX-70027888-CCCTCCAGGACCCCCAGGA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EDA	NM_001399.5	c.572_589del	p.Pro191_Pro196del	inframe_deletion	4/8	ENST00000374552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDA	ENST00000374552.9	c.572_589del	p.Pro191_Pro196del	inframe_deletion	4/8	1	NM_001399.5	P4

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

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: 0.0000211

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000145

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 21

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 08, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 10, 2012	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. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 21, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 08, 2024	Criteria applied: PS4,PM1,PM4,PS2_SUP,PM2_SUP -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 25, 2024	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 25, 2021	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; In-frame deletion of 6 amino acids in a non-repeat region; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 26345974, 20979233, 11279189, 31924237, 31796081, 30394555, 27305980, 9736768) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2021	- -

EDA-related condition Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 26, 2024

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. -

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: rs397516668; hg19: chrX-69247738;