ClinVar Miner

Submissions for variant NM_001399.5(EDA):c.467G>A (p.Arg156His) (rs132630314)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000032612 SCV000060828 pathogenic Hypohidrotic X-linked ectodermal dysplasia 2011-09-04 criteria provided, single submitter clinical testing The Arg156His variant in EDA has been reported in at least 18 individuals with X -linked hypohidrotic ectodermal dysplasia (Schneider 2001, Monreal 1998, Schneid er 2011, Vincent 2001, Zhao 2008). This variant was reported as de novo in at le ast 4 individuals with de novo disease and was reported in an individual with a family history of X-linked hypohidrotic ectodermal dysplasia (Schneider 2001, Vi ncent 2001). Furthermore, functional studies have shown that the change to Histi dine (His) at position 156 affects protein cleavage (Chen 2001, Elomaa 2001). In summary, this variant meets our criteria to be classified as pathogenic.
GeneDx RCV000255365 SCV000321580 pathogenic not provided 2018-04-27 criteria provided, single submitter clinical testing The R156H missense variant in the EDA1 gene has been reported previously in association with X-linked HED (Monreal et al., 1998). Arginine 156 lies in the positively charged domain of the encoded ectodysplasin protein, which is highly conserved and functionally important, and this residue is a mutational hot spot in EDA1. Functional studies of the R156H variant have shown that it impairs the cleavage of furin and, thus, sweat production (Schneider et al., 2011). Missense variants at the same codon (R156S/C/L) and in nearby residues (R153C/H, R155C, K158N) have also been reported in the Human Gene Mutation Database in association with EDA1-related disorders (Stenson et al., 2014). Therefore, the R156H missense variant is interpreted as pathogenic.
Invitae RCV000032612 SCV000630027 pathogenic Hypohidrotic X-linked ectodermal dysplasia 2019-10-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 156 of the EDA protein (p.Arg156His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (rs132630314, ExAC no frequency). This variant has been reported in multiple individuals affected with hypohidrotic ectodermal dysplasia (PMID: 11416205, 11279189, 9683615, 18231121, 11295832). This variant is also known as c.708G>A (p.R156H) in the literature. ClinVar contains an entry for this variant (Variation ID: 11037). Experimental studies have shown that this missense change inhibits cleavage of EDA, which disrupts its activity (PMID: 11416205). A different missense substitution at this codon (p.Arg156Cys) has been determined to be pathogenic (PMID: 11416205, 11279189, 9683615). This suggests that the arginine residue is critical for EDA protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000032612 SCV000056366 pathogenic Hypohidrotic X-linked ectodermal dysplasia 2009-07-01 no assertion criteria provided literature only

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