ClinVar Miner

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

gnomAD frequency: 0.00057  dbSNP: rs148412639
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000616942 SCV000712930 likely pathogenic Hereditary xanthinuria type 1 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:/ /exac.broadinstitute.org; 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.
Invitae RCV000685712 SCV000813204 likely pathogenic Xanthinuria type II 2024-01-15 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. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in XDH are known to be pathogenic (PMID: 9153281). This variant is present in population databases (rs148412639, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with XDH-related conditions. ClinVar contains an entry for this variant (Variation ID: 505602). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Illumina Laboratory Services, Illumina RCV000616942 SCV000915913 uncertain significance Hereditary xanthinuria type 1 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.
Revvity Omics, Revvity Omics RCV000616942 SCV002017951 likely pathogenic Hereditary xanthinuria type 1 2020-05-11 criteria provided, single submitter clinical testing
GeneDx RCV003156264 SCV003845584 uncertain significance not provided 2023-03-24 criteria provided, single submitter clinical testing Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown; Has not been previously published as pathogenic or benign in association with xanthinuria to our knowledge; This variant is associated with the following publications: (PMID: 31589614, 30609409, 31980526, 31345219)

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.