ClinVar Miner

Submissions for variant NM_001029896.2(WDR45):c.746CCT[1] (p.Ser250del)

dbSNP: rs1064793294
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000486845 SCV000565661 pathogenic not provided 2022-09-04 criteria provided, single submitter clinical testing Not observed in large population cohorts (gnomAD); In-frame deletion of 1 amino acids in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24368176, 26577041, 28371320, 26633542, 29445477)
Invitae RCV001242357 SCV001415439 pathogenic Neurodegeneration with brain iron accumulation 5 2023-06-14 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 418542). This variant has been observed in individual(s) with neurodegeneration with brain iron accumulation (PMID: 24368176, 28371320). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This variant, c.752_754del, results in the deletion of 1 amino acid(s) of the WDR45 protein (p.Ser251del), but otherwise preserves the integrity of the reading frame.
Ambry Genetics RCV001266673 SCV001444850 likely pathogenic Inborn genetic diseases 2018-03-09 criteria provided, single submitter clinical testing
Mendelics RCV001242357 SCV002519971 pathogenic Neurodegeneration with brain iron accumulation 5 2022-05-04 criteria provided, single submitter clinical testing
Clinical Genomics Program, Stanford Medicine RCV001242357 SCV001427088 pathogenic Neurodegeneration with brain iron accumulation 5 2019-10-08 no assertion criteria provided clinical testing The p.Ser251del variant in the WDR45 gene has been previously reported in 5 unrelated individuals with BPAN or WDR45-associated clinical features (Verhoeven et al., 2014; Redon et al., 2017; ClinVar Accession VCV000418542.2; GeneDx, personal communication, October 3, 2019). In three of these reported individuals, the p.Ser251del variant occurred de novo. This variant was absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). The p.Ser251del variant results in an in-frame deletion of 1 amino acid, and computational tools predict that this variant is deleterious; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Ser251del variant as pathogenic for X-linked Beta-propeller protein-associated neurodegeneration based on the information above. [ACMG evidence codes used: PS2_VeryStrong; PM2; PP3]

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