ClinVar Miner

Submissions for variant NM_024570.4(RNASEH2B):c.698+1G>A

gnomAD frequency: 0.00001  dbSNP: rs367915667
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics RCV000516648 SCV000614884 likely pathogenic not provided 2017-10-25 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001192743 SCV001361051 likely pathogenic Aicardi Goutieres syndrome 2019-09-04 criteria provided, single submitter clinical testing Variant summary: RNASEH2B c.698+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: four predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 3.2e-05 in 31368 control chromosomes (gnomAD, genomes dataset). To our knowledge, no occurrence of c.698+1G>A in individuals affected with Aicardi Goutieres syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV001857924 SCV002294818 likely pathogenic Aicardi-Goutieres syndrome 2 2023-12-01 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 8 of the RNASEH2B 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 RNASEH2B are known to be pathogenic (PMID: 17846997). This variant is present in population databases (rs367915667, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with RNASEH2B-related conditions. ClinVar contains an entry for this variant (Variation ID: 448169). 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.
Fulgent Genetics, Fulgent Genetics RCV001857924 SCV005636581 likely pathogenic Aicardi-Goutieres syndrome 2 2024-03-07 criteria provided, single submitter clinical testing

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