chrX-70027937-C-T

Variant names:

• chrX-70027937-C-T
• rs397516671
• NM_001399.5:c.607C>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.607C>T​(p.Pro203Ser) variant causes a missense change. 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. P203A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 21)
• Consequence: EDA NM_001399.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.09
• Publications: 1 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 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 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-70027937-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1190348.Status of the report is criteria_provided_single_submitter, 1 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, 0.762
• PP5: Variant X-70027937-C-T is Pathogenic according to our data. Variant chrX-70027937-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 44203.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.607C>T	p.Pro203Ser	missense	Exon 4 of 8	NP_001390.1
	EDA	NM_001005609.2		c.607C>T	p.Pro203Ser	missense	Exon 4 of 8	NP_001005609.1
	EDA	NM_001440761.1		c.607C>T	p.Pro203Ser	missense	Exon 4 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.607C>T	p.Pro203Ser	missense	Exon 4 of 8	ENSP00000363680.4
	EDA	ENST00000374553.6	TSL:1	c.607C>T	p.Pro203Ser	missense	Exon 4 of 8	ENSP00000363681.2
	EDA	ENST00000524573.5	TSL:1	c.607C>T	p.Pro203Ser	missense	Exon 4 of 8	ENSP00000432585.1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 21

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypohidrotic X-linked ectodermal dysplasia Pathogenic:2

Dec 20, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 203 of the EDA protein (p.Pro203Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with EDA-related conditions. ClinVar contains an entry for this variant (Variation ID: 44203). 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. This variant disrupts the p.Pro203 amino acid residue in EDA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27305980; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

May 18, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Pro203Ser variant in EDA has not been reported in the literature nor previou sly identified by our laboratory. Computational analyses (biochemical amino aci d properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that this va riant may impact the protein, though this information is not predictive enough t o determine pathogenicity. Other mutations affecting nearby residues and also af fecting nearby proline residues have been associated to EDA increasing the likel ihood that this mutation is pathogenic. Furthermore, the presence of this mutati on in a patient with features of hypohidrotic ectodermal dysplasia and an X-link ed family history further supports the likelihood that this variant is pathogeni c. In summary, although additional data is needed to fully assess its clinical s ignificance, this variant is more likely pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Benign	1.9	L
PhyloP100		7.1
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.53
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.019	D
Polyphen		1.0	D
Vest4		0.42
MutPred		0.34		Gain of glycosylation at P203 (P = 0.0053)
MVP		0.98
MPC		0.79
ClinPred		0.89	D
GERP RS		4.7
Varity_R		0.83
gMVP		0.91
Mutation Taster		=34/66	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs397516671; hg19: chrX-69247787;