rs397516672

Positions:

• chrX-70029527-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001399.5(EDA):​c.730C>T​(p.Arg244*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 24)
• Consequence: EDA NM_001399.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 1.62

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-70029527-C-T is Pathogenic according to our data. Variant chrX-70029527-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 44205.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-70029527-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EDA	NM_001399.5	c.730C>T	p.Arg244*	stop_gained	5/8	ENST00000374552.9	NP_001390.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EDA	ENST00000374552.9	c.730C>T	p.Arg244*	stop_gained	5/8	1	NM_001399.5	ENSP00000363680.4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 24

ClinVar

Significance: 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	Aug 24, 2012	The p.Arg244X variant in EDA has been reported two females with clinical feature s of hypohidrotic ectodermal dysplasia (HED) and segregated with disease in an a ffected sister of one of these probands (Vincent 2001). It was absent from large population studies. This nonsense variant leads to a premature termination codo n at position 244, which is predicted to lead to a truncated or absent protein. Loss of function of the EDA gene is an established disease mechanism in XLHED. I n summary, this variant meets our criteria to be classified as pathogenic for HE D in an X-linked manner (http://www.partners.org/personalizedmedicine/LMM) based upon segregation studies, absence from controls, and predicted impact to the pr otein. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 19, 2022	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 44205). This premature translational stop signal has been observed in individuals with hypohidrotic ectodermal dysplasia (PMID: 11378824, 22032522). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg244*) in the EDA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in EDA are known to be pathogenic (PMID: 9683615). -

EDA-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 19, 2024

The EDA c.730C>T variant is predicted to result in premature protein termination (p.Arg244*). This variant was reported in four heterozygous females from two apparently unrelated families, segregating with features of ectodermal dysplasia (Vincent et al 2001. PubMed ID: 11378824). This variant was also reported in a hemizygous male with ectodermal dysplasia (Zhu T et al 2020. PubMed ID: 33240318, Suppl Data Sheet 2). This variant has not been reported in a large population database, indicating it is rare. Nonsense variants in EDA are expected to be pathogenic. This variant is interpreted as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 23, 2015

The R244X nonsense variant in the EDA1 gene has been reported previously in association with X-linked HED (Vincent et al., 2001). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. We interpret the R244X variant to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	37
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.90	D
Vest4		0.98
GERP RS		1.6

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs397516672; hg19: chrX-69249377;