Submissions for variant NM_001399.5(EDA):c.730C>T (p.Arg244Ter)

dbSNP: rs397516672

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037183	SCV000060840	pathogenic	Hypohidrotic X-linked ectodermal dysplasia	2012-08-24	criteria provided, single submitter	clinical testing	The p.Arg244X variant in EDA has been reported two females with clinical feature s of hypohidrotic ectodermal dysplasia (HED) and segregated with disease in an a ffected sister of one of these probands (Vincent 2001). It was absent from large population studies. This nonsense variant leads to a premature termination codo n at position 244, which is predicted to lead to a truncated or absent protein. Loss of function of the EDA gene is an established disease mechanism in XLHED. I n summary, this variant meets our criteria to be classified as pathogenic for HE D in an X-linked manner (http://www.partners.org/personalizedmedicine/LMM) based upon segregation studies, absence from controls, and predicted impact to the pr otein.
GeneDx	RCV000255016	SCV000321582	pathogenic	not provided	2015-03-23	criteria provided, single submitter	clinical testing	The R244X nonsense variant in the EDA1 gene has been reported previously in association with X-linked HED (Vincent et al., 2001). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. We interpret the R244X variant to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000037183	SCV001220141	pathogenic	Hypohidrotic X-linked ectodermal dysplasia	2022-08-19	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 44205). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with hypohidrotic ectodermal dysplasia (PMID: 11378824, 22032522). This sequence change creates a premature translational stop signal (p.Arg244*) in the EDA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in EDA are known to be pathogenic (PMID: 9683615). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003904912	SCV004725140	pathogenic	EDA-related disorder	2024-01-19	no assertion criteria provided	clinical testing	The EDA c.730C>T variant is predicted to result in premature protein termination (p.Arg244*). This variant was reported in four heterozygous females from two apparently unrelated families, segregating with features of ectodermal dysplasia (Vincent et al 2001. PubMed ID: 11378824). This variant was also reported in a hemizygous male with ectodermal dysplasia (Zhu T et al 2020. PubMed ID: 33240318, Suppl Data Sheet 2). This variant has not been reported in a large population database, indicating it is rare. Nonsense variants in EDA are expected to be pathogenic. This variant is interpreted as pathogenic.