ClinVar Miner

Submissions for variant NM_000379.4(XDH):c.1686+1G>C (rs148412639)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000616942 SCV000915913 uncertain significance Deficiency of xanthine oxidase 2018-10-21 criteria provided, single submitter clinical testing This variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. It was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018) and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score for this variant, it could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene and cDNA change. No publications were found based on this search. Due to the potential impact of splice donor variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for this disease.
Invitae RCV000685712 SCV000813204 likely pathogenic Xanthinuria type 2 2018-06-15 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 16 of the XDH gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs148412639, ExAC 0.08%). This variant has not been reported in the literature in individuals with XDH-related disease. ClinVar contains an entry for this variant (Variation ID: 505602). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in XDH are known to be pathogenic (PMID: 9153281). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000616942 SCV000712930 likely pathogenic Deficiency of xanthine oxidase 2017-02-16 criteria provided, single submitter clinical testing The c.1686+1G>C (NM_000379.3 c.1686+1G>C) variant in XDH has not been reported i n individuals with xanthinuria. This variant has been identified in 0.076% (50/6 5,368) of European chromosomes by the Exome Aggregation Consortium (ExAC, http:/ /; dbSNP rs148412639). Although this variant has been see n in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant occurs in the invariant region (+/- 1 /2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Biallelic loss of function of the XDH gene has been associated with xanthinuria type I. In summary, although additiona l studies are required to fully establish its null effect, the c.1686+1G>C varia nt is likely pathogenic for xanthinuria, type I based upon its predicted functio nal impact.

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