rs121908451
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3_Strong
The ENST00000258443.7(EDAR):āc.259T>Cā(p.Cys87Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,614,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C87G) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000258443.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
EDAR | NM_022336.4 | c.259T>C | p.Cys87Arg | missense_variant | 4/12 | ENST00000258443.7 | NP_071731.1 | |
EDAR | XM_006712204.2 | c.259T>C | p.Cys87Arg | missense_variant | 4/11 | XP_006712267.1 | ||
RANBP2 | XM_047445367.1 | c.8370+156249A>G | intron_variant | XP_047301323.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
EDAR | ENST00000258443.7 | c.259T>C | p.Cys87Arg | missense_variant | 4/12 | 1 | NM_022336.4 | ENSP00000258443 | P1 | |
EDAR | ENST00000376651.1 | c.259T>C | p.Cys87Arg | missense_variant | 4/11 | 2 | ENSP00000365839 | |||
EDAR | ENST00000409271.5 | c.259T>C | p.Cys87Arg | missense_variant | 5/12 | 2 | ENSP00000386371 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152188Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251362Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135896
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461862Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727234
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152188Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74354
ClinVar
Submissions by phenotype
Ectodermal dysplasia 10B, hypohidrotic/hair/tooth type, autosomal recessive Pathogenic:1Uncertain:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 1999 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | The EDAR c.259T>C (p.Cys87Arg) variant has been reported in one study in which it is found in a homozygous state in one individual with autosomal recessive hypohidrotic ectodermal dysplasia and in a heterozygous state in both unaffected parents (Monreal et al. 1999). The p.Cys87Arg variant was absent from 100 control chromosomes but is reported at a frequency of 0.00003 in the European (non-Finnish) population of the Exome Aggregation Consortium. This is based on two alleles only in a region of good sequence coverage so the variant is presumed to be rare. In vitro expression testing found that the p.Cys87Arg variant abolished EDAR binding to EDA-A1 and had a low yield recovery indicating defective folding or solubility (Schneider et al. 2001). Based on the evidence, the p.Cys87Arg variant is classified as a variant of unknown significance but suspicious for pathogenicity for autosomal recessive hypohidrotic ectodermal dysplasia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Autosomal recessive hypohidrotic ectodermal dysplasia syndrome;C3888065:Ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 10, 2023 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change affects EDAR function (PMID: 11279189). 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 EDAR protein function. ClinVar contains an entry for this variant (Variation ID: 5851). This missense change has been observed in individual(s) with hypohidrotic ectodermal dysplasia (PMID: 10431241). This variant is present in population databases (rs121908451, gnomAD 0.004%). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 87 of the EDAR protein (p.Cys87Arg). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at