ClinVar Miner

Submissions for variant NM_001399.5(EDA):c.463C>T (p.Arg155Cys) (rs132630312)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000011782 SCV000060827 pathogenic Hypohidrotic X-linked ectodermal dysplasia 2015-06-10 criteria provided, single submitter clinical testing The p.Arg155Cys variant in EDA has been reported in 6 affected males with X-link ed hypohidrotic ectodermal dysplasia (XLHED) and segregated with disease in 1 af fected male and 5 carrier females from 3 families (Monreal 1998, Schneider 2001, Fan 2008, Khabour 2010, Callea 2013, Zhu 2013). It was absent from large popula tion studies. Furthermore, this variant has been identified by our laboratory in 5 individuals with XLHED. This variant resides in the furin domain of EDA and i n-vitro functional studies suggest that this variant impacts protein cleavage (C hen, 2001). In summary, this variant meets our criteria to be classified as path ogenic for XLHED based upon segregation studies, absence from controls, and func tional evidence.
GeneDx RCV000254983 SCV000321579 pathogenic not provided 2018-06-15 criteria provided, single submitter clinical testing The R155C variant in the EDA gene has been reported previously in association with X-linked hypohidrotic ectodermal dysplasia (HED) (Monreal et al., 1998; Schneider et al., 2001; Khabour et al., 2010) and has been observed before by GeneDx in multiple patients referred for EDA gene testing. The R155C variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R155C variant is a non-conservative amino acid substitution, which occurs at a position within the furin recognition sequence. The gain of a Cysteine residue at amino acid position 155 is likely to affect disulfide bond formation, and variants within the furin recognition sequence have been shown in functional studies to prevent cleavage of EDA, which appears necessary for EDA-mediated cell-to-cell signaling (Schneider et al., 2001; Chen et al., 2001). Pathogenic variants within this region, most often at residue Arginine 156 (R156G, R156C, R156S, R156L, R156H), cause approximately 20% of all reported cases of X-linked hypohidrotic ectodermal dysplasia (Chen et al., 2001; Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret R155C as a pathogenic variant.
Invitae RCV000011782 SCV000630025 pathogenic Hypohidrotic X-linked ectodermal dysplasia 2018-12-07 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 155 of the EDA protein (p.Arg155Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in multiple individuals with X-linked hypohidrotic ectodermal dsyplasia (XLHED) (PMID: 9683615, 22428923, 26273176, 27305980, 18231121). This variant segregated with disease in several families with males that are affected with XLHED and female carriers that were either unaffected or mildly affected (PMID: 18821982, 20486090, 25333067). This variant has also been observed to occur as a de novo change in one individual with XLHED (PMID: 27054699). ClinVar contains an entry for this variant (Variation ID: 11035). Experimental evidence suggests this variant shows a lower catalytic efficiency compared to wild type EDA protein (PMID: 11416205). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000763630 SCV000894498 pathogenic Hypohidrotic X-linked ectodermal dysplasia; Tooth agenesis, selective, X-linked, 1 2018-10-31 criteria provided, single submitter clinical testing
OMIM RCV000011782 SCV000032014 pathogenic Hypohidrotic X-linked ectodermal dysplasia 1998-08-01 no assertion criteria provided literature only

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