ClinVar Miner

Submissions for variant NM_000124.4(ERCC6):c.1526+1G>T (rs371739894)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Claritas Genomics RCV000170365 SCV000222777 pathogenic Cockayne syndrome B 2012-01-09 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000723622 SCV000231476 pathogenic not provided 2016-11-29 criteria provided, single submitter clinical testing
Invitae RCV000723622 SCV000961578 likely pathogenic not provided 2018-10-24 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 6 of the ERCC6 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 (rs371739894, ExAC 0.005%). This variant has been observed in combination with another ERCC6 variant in an individual affected with Cockayne syndrome (PMID: 29572252). ClinVar contains an entry for this variant (Variation ID: 190147). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ERCC6 are known to be pathogenic (PMID: 9443879, 18628313). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001280930 SCV001468275 likely pathogenic Cockayne syndrome 2020-12-29 criteria provided, single submitter clinical testing Variant summary: ERCC6 c.1526+1G>T 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 1.2e-05 in 250636 control chromosomes. c.1526+1G>T has been reported in the literature in at-least one individual affected with Cockayne Syndrome (Calmels_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=1)/likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Counsyl RCV000983983 SCV000790451 likely pathogenic DE SANCTIS-CACCHIONE SYNDROME 2019-06-24 no assertion criteria provided clinical testing

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