NC_000023.11:g.70027902_70027919del AND Hypohidrotic X-linked ectodermal dysplasia

Germline classification:: Pathogenic (6 submissions)
Last evaluated:: Jan 29, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000633503.19

Allele description [Variation Report for NC_000023.11:g.70027902_70027919del]

NC_000023.11:g.70027902_70027919del

Gene:

EDA:ectodysplasin A [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

Xq13.1

Genomic location:

Preferred name:

NC_000023.11:g.70027902_70027919del

HGVS:

NC_000023.11:g.70027902_70027919del
NG_009809.2:g.416836_416853del
NM_001005609.2:c.572_589del
NM_001005612.3:c.572_589del
NM_001399.5:c.572_589delMANE SELECT
NP_001005609.1:p.188_190PGP[1]
NP_001005612.2:p.188_190PGP[1]
NP_001390.1:p.188_190PGP[1]
NC_000023.10:g.69247739_69247756del
NC_000023.10:g.69247752_69247769del
NM_001399.4:c.572_589delCAGGACCTCCAGGACCCC
c.572_589del

Links:

dbSNP: rs397516668

NCBI 1000 Genomes Browser:

rs397516668

Observations:

Condition(s)

Name:: Hypohidrotic X-linked ectodermal dysplasia (XHED)
Synonyms:: ECTODERMAL DYSPLASIA, HYPOHIDROTIC, 1; Anhidrotic ectodermal dysplasia X-linked; Christ Siemens Touraine syndrome; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010585; MedGen: C0162359; Orphanet: 181; Orphanet: 238468; OMIM: 305100

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000060835	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Apr 10, 2012)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 9736768, 20979233, 24033266
SCV000754739	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 29, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 9736768, 11279189, 27305980, 28492532
SCV002087202	Natera, Inc.	no assertion criteria provided	Pathogenic (Oct 21, 2020)	germline	clinical testing
SCV002103648	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Feb 8, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 9736768, 31796081, 11279189, 31924237 Citation Link,
SCV004242417	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 8, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	2	1	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Only four genes (EDA1, EDAR, EDARADD, and WNT10A) account for 90% of hypohidrotic/anhidrotic ectodermal dysplasia cases.

Cluzeau C, Hadj-Rabia S, Jambou M, Mansour S, Guigue P, Masmoudi S, Bal E, Chassaing N, Vincent MC, Viot G, Clauss F, Manière MC, Toupenay S, Le Merrer M, Lyonnet S, Cormier-Daire V, Amiel J, Faivre L, de Prost Y, Munnich A, Bonnefont JP, Bodemer C, et al.

Hum Mutat. 2011 Jan;32(1):70-2. doi: 10.1002/humu.21384.

PubMed [citation]

PMID:: 20979233

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

See all PubMed Citations (9)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000060835.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (3)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		2	not provided	1	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000754739.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV002087202.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002103648.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Human Genetics, University of Leipzig Medical Center, SCV004242417.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, SCV004806459.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Flagged submissions

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004806459	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	flagged submission Reason: Outlier claim with insufficient supporting evidence Notes: None (ACMG Guidelines, 2015)	Uncertain significance (Mar 25, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004806459

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

flagged submission

Reason: Outlier claim with insufficient supporting evidence

Notes: None

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 25, 2024)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Last Updated: Oct 13, 2024

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