ClinVar Miner

Submissions for variant NM_000124.4(ERCC6):c.2599-26A>G

gnomAD frequency: 0.00006  dbSNP: rs4253196
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Claritas Genomics RCV000170380 SCV000222796 pathogenic Cockayne syndrome type 2 2012-04-17 criteria provided, single submitter clinical testing
Baylor Genetics RCV000170380 SCV000807605 pathogenic Cockayne syndrome type 2 2017-09-01 criteria provided, single submitter clinical testing This mutation has been previously reported as disease-causing and was found once in our laboratory in trans with another pathogenic mutation in a patient with suspected diagnosis of Cockayne syndrome. Heterozygotes are expected to be asymptomatic carriers.
Invitae RCV001236817 SCV001409554 pathogenic not provided 2024-01-11 criteria provided, single submitter clinical testing This sequence change falls in intron 13 of the ERCC6 gene. It does not directly change the encoded amino acid sequence of the ERCC6 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs4253196, gnomAD 0.01%). This variant has been observed in individual(s) with Cockayne syndrome (PMID: 19894250, 27004399, 29572252). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 190162). Studies have shown that this variant results in partial insertion of intron 13 into the mRNA and introduces a premature termination codon (PMID: 9443879, 29572252). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000170380 SCV001443763 likely pathogenic Cockayne syndrome type 2 2020-03-02 criteria provided, single submitter clinical testing This variant has been previously reported as a compound heterozygous change in five individuals and as a homozygous change in one individual with Cockayne Syndrome (PMID: 19894250, 29572252). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0053% (15/282404) and thus is presumed to be rare. Multiple splice prediction tools suggest this variant is likely to interfere with normal splicing. Based on the available evidence, the c.2599-26A>G variant is classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002271444 SCV002555598 pathogenic Cockayne syndrome 2022-06-03 criteria provided, single submitter clinical testing Variant summary: ERCC6 c.2599-26A>G is located at a position not widely known to affect splicing. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates a cryptic 3 acceptor site. At least two publications report experimental evidence that this variant affects mRNA splicing and results in a 25-bp insertion corresponding to the end of intron 13, predicted as p.Met867ThrfsX14. The variant allele was found at a frequency of 5.2e-05 in 251018 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ERCC6 causing Cockayne Syndrome (5.2e-05 vs 0.0016), allowing no conclusion about variant significance. c.2599-26A>G has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with Cockayne Syndrome (Mallery_1998, Laugel_2010, Calmels_2018). These data indicate that the variant is very likely to be associated with disease. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=1), likely pathogenic (n=1) and pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.
Counsyl RCV000666576 SCV000790886 uncertain significance DE SANCTIS-CACCHIONE SYNDROME; Cerebrooculofacioskeletal syndrome 1; Cockayne syndrome type 2 2017-04-14 flagged submission clinical testing

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