X-70035500-C-T

Variant names:

• chrX-70035500-C-T
• rs876657639
• NM_001399.5:c.1067C>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP2 PP3 PP5_Very_Strong

The NM_001399.5(EDA):​c.1067C>T​(p.Ala356Val) variant causes a missense change involving the alteration of a 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A356D) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 21)
• Consequence: EDA NM_001399.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.29
• Publications: 3 publications found

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]

EDA Gene-Disease associations (from GenCC):

• tooth agenesis, selective, X-linked, 1

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• X-linked hypohidrotic ectodermal dysplasia

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• tooth agenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_001399.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-70035500-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1072864.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 110 curated pathogenic missense variants (we use a threshold of 10). The gene has 22 curated benign missense variants. Gene score misZ: 1.7843 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to tooth agenesis, selective, X-linked, 1, X-linked hypohidrotic ectodermal dysplasia, tooth agenesis.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.816
• PP5: Variant X-70035500-C-T is Pathogenic according to our data. Variant chrX-70035500-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 228255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001399.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDA	NM_001399.5	MANE Select	c.1067C>T	p.Ala356Val	missense	Exon 8 of 8	NP_001390.1
	EDA	NM_001005609.2		c.1061C>T	p.Ala354Val	missense	Exon 8 of 8	NP_001005609.1
	EDA	NM_001440761.1		c.1058C>T	p.Ala353Val	missense	Exon 8 of 8	NP_001427690.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDA	ENST00000374552.9	TSL:1 MANE Select	c.1067C>T	p.Ala356Val	missense	Exon 8 of 8	ENSP00000363680.4
	EDA	ENST00000374553.6	TSL:1	c.1061C>T	p.Ala354Val	missense	Exon 8 of 8	ENSP00000363681.2
	EDA	ENST00000524573.5	TSL:1	c.1052C>T	p.Ala351Val	missense	Exon 8 of 8	ENSP00000432585.1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 21

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypohidrotic X-linked ectodermal dysplasia Pathogenic:2

Jan 26, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ala356Val variant in EDA has been reported in 2 individuals with clinical features of X-linked hypohidrotic ectodermaldysplasia (XLHED)(Clauss 2010, Cluze au 2011) and was absent from large population studies. In addition, a different amino acid change at the same position (p.Ala356Asn) has been identified in 1 ma le with XLHED suggesting that a change at this position may not be tolerated (Mo nreal 2008). Computational prediction tools and conservation analysis suggest th at the p.Ala356Val variant may impact the protein, though this information is no t predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, the p.Ala356V al variant is likely pathogenic.

Nov 19, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine with valine at codon 356 of the EDA protein (p.Ala356Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ala356 amino acid residue in EDA. Other variant(s) that disrupt this residue have been observed in individuals with EDA-related conditions (PMID: 9683615, 11279189), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in an individual affected with hypohidrotic ectodermal dysplasia (PMID: 20979233). ClinVar contains an entry for this variant (Variation ID: 228255). This variant is not present in population databases (ExAC no frequency).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.76	D
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Benign	1.3	L
PhyloP100		7.3
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.4	N
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.59
MutPred		0.70		Gain of methylation at K355 (P = 0.0379)
MVP		0.99
MPC		1.8
ClinPred		0.98	D
GERP RS		5.4
Varity_R		0.96
gMVP		0.93
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs876657639; hg19: chrX-69255350; COSMIC: COSV108225728; COSMIC: COSV108225728;