NM_001399.5(EDA):c.826C>T (p.Arg276Cys) AND Hypohidrotic X-linked ectodermal dysplasia

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Feb 4, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000024599.10

Allele description [Variation Report for NM_001399.5(EDA):c.826C>T (p.Arg276Cys)]

NM_001399.5(EDA):c.826C>T (p.Arg276Cys)

Gene:

EDA:ectodysplasin A [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xq13.1

Genomic location:

Preferred name:

NM_001399.5(EDA):c.826C>T (p.Arg276Cys)

HGVS:

NC_000023.11:g.70033430C>T
NG_009809.2:g.422364C>T
NM_001005609.2:c.826C>T
NM_001005612.3:c.817C>T
NM_001399.5:c.826C>TMANE SELECT
NP_001005609.1:p.Arg276Cys
NP_001005612.2:p.Arg273Cys
NP_001390.1:p.Arg276Cys
NC_000023.10:g.69253280C>T
NM_001399.4:c.826C>T

Protein change:

R273C; ARG276CYS

Links:

OMIM: 300451.0019; dbSNP: rs387907197

NCBI 1000 Genomes Browser:

rs387907197

Molecular consequence:

NM_001005609.2:c.826C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001005612.3:c.817C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001399.5:c.826C>T - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000045908	OMIM	no assertion criteria provided	Pathogenic (Dec 1, 2009)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV001577431	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Feb 4, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 19921643, 21357618, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000045908

OMIM

no assertion criteria provided

Pathogenic
(Dec 1, 2009)

germline

literature only

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

SCV001577431

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Feb 4, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Father-to-son transmission of an X-linked gene: a case of paternal sex chromosome heterodisomy.

Ferrier RA, Lowry RB, Lemire EG, Stoeber GP, Howard J, Parboosingh JS.

Am J Med Genet A. 2009 Dec;149A(12):2871-3. doi: 10.1002/ajmg.a.32994. No abstract available.

PubMed [citation]

PMID:: 19921643

Sweating ability and genotype in individuals with X-linked hypohidrotic ectodermal dysplasia.

Schneider H, Hammersen J, Preisler-Adams S, Huttner K, Rascher W, Bohring A.

J Med Genet. 2011 Jun;48(6):426-32. doi: 10.1136/jmg.2010.084012. Epub 2011 Feb 26.

PubMed [citation]

PMID:: 21357618

See all PubMed Citations (3)

Details of each submission

From OMIM, SCV000045908.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a boy and his affected father with X-linked hypohidrotic ectodermal dysplasia (XHED; 305100), Ferrier et al. (2009) detected hemizygosity for an 826C-T transition in exon 7, resulting in an arg276-to-cys (R276C) substitution. Results of analysis of polymorphic X chromosome markers were consistent with paternal inheritance of the X chromosome. Family history revealed an affected paternal great-great uncle, a male first cousin once removed, and 2 male second cousins. Analysis of the EDA gene in the 2 second cousins showed hemizygosity for the R276 mutation, which was inherited from their carrier mother.

#	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		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001577431.4

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

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg276 amino acid residue in EDA. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt EDA protein function. ClinVar contains an entry for this variant (Variation ID: 31908). This missense change has been observed in individuals with clinical features of, or diagnosis of, ectodermal dysplasia (PMID: 19921643, 21357618; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 276 of the EDA protein (p.Arg276Cys).

#	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

Last Updated: Oct 20, 2024

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