ClinVar Miner

Submissions for variant NM_001399.5(EDA):c.1094T>C (p.Val365Ala) (rs397516654)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000037161 SCV000060818 likely pathogenic Partial congenital absence of teeth 2011-09-20 criteria provided, single submitter clinical testing The Val365Ala variant in EDA has been reported in one family with X-linked non-s yndromic tooth agenesis, showing segregation with clinical features in at least 6 meioses in this family. In addition, this variant was absent from over 140 co ntrol chromosomes (Mues 2010). Valine (Val) at position 365 is highly conserved across evolutionarily distant species suggesting that a change to the amino acid may not be tolerated. However, computational analyses (biochemical amino acid properties, homology, PolyPhen2, SIFT, AlignGVGD) do not provide strong support for or against pathogenicity. Furthermore, functional studies suggest that the Val365Arg variant may affect cell signaling pathways, but does not show the same decrease in receptor binding seen in classic HED variants (Mues 2010). In summ ary, this variant is likely to be pathogenic in association with tooth agenesis, but its role the hypohidrotic ectodermal dysplasia phenotype remains unclear.
Invitae RCV000542700 SCV000630019 pathogenic Hypohidrotic X-linked ectodermal dysplasia 2019-02-27 criteria provided, single submitter clinical testing This sequence change replaces valine with alanine at codon 365 of the EDA protein (p.Val365Ala). The valine residue is highly conserved and there is a small physicochemical difference between valine and alanine. This variant is not present in population databases (rs397516654, ExAC no frequency). This variant has been reported to segregate with selective tooth agenesis in a single, large family (PMID: 19623212). ClinVar contains an entry for this variant (Variation ID: 44185). Experimental studies have shown that this missense change does not affect protein modification or secretion, but does disrupt the downstream function of EDA in cell culture (PMID: 19623212). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000624502 SCV000741907 likely pathogenic Inborn genetic diseases 2017-03-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: LIKELY POSITIVE: Relevant Alteration(s) Detected

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