rs397516670

chrX-70027984-TCCTCCAGGTCCTCCTGGTCCTCAAGGACCCCCTGG-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001399.5(EDA):c.663_697del(p.Pro222ThrfsTer6) variant causes a frameshift change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 21)
• Consequence: EDA NM_001399.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• 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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant X-70027984-TCCTCCAGGTCCTCCTGGTCCTCAAGGACCCCCTGG-T is Pathogenic according to our data. Variant chrX-70027984-TCCTCCAGGTCCTCCTGGTCCTCAAGGACCCCCTGG-T is described in ClinVar as [Pathogenic]. Clinvar id is 44202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-70027984-TCCTCCAGGTCCTCCTGGTCCTCAAGGACCCCCTGG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EDA	NM_001399.5	c.663_697del	p.Pro222ThrfsTer6	frameshift_variant	4/8	ENST00000374552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDA	ENST00000374552.9	c.663_697del	p.Pro222ThrfsTer6	frameshift_variant	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

Submissions summary: Pathogenic:3

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	Sep 27, 2011	The Pro222fs variant in EDA has not been reported in the literature nor previous ly identified by our laboratory. The Pro222fs variant is predicted to cause a f rameshift, which alters the protein's amino acid sequence beginning at codon 222 and leads to a premature stop codon 6 codons downstream. This alteration is the n predicted to lead to a truncated or absent protein. In summary, this variant m eets our criteria to be classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jun 12, 2017	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in EDA are known to be pathogenic (PMID: 9683615). This variant has been reported to be de novo in an individual affected with X-linked hypohidrotic ectodermal dysplasia (PMID: 9683615). This variant is also known as c.904_938del in the literature. ClinVar contains an entry for this variant (Variation ID: 44202). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Pro222Thrfs*6) in the EDA gene. It is expected to result in an absent or disrupted protein product. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 03, 2018

The c.663_697del35 variant, which is alternatively described as c.904_938del35 using alternate nomenclature, has been reported previously in patients with HED (Monreal et al., 1998). The variant causes a frameshift starting with codon Proline 222, changing it to a Threonine, and creates a premature Stop codon at position 6 of the new reading frame, denoted p.Pro222ThrfsX6. This pathogenic variant is expected to result in nonsense-mediated mRNA decay or in protein truncation. The variant 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. -

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: rs397516670; hg19: chrX-69247834;