ClinVar Miner

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

gnomAD frequency: 0.00003  dbSNP: rs371739894
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Claritas Genomics RCV000170365 SCV000222777 pathogenic Cockayne syndrome type 2 2012-01-09 criteria provided, single submitter clinical testing
Eurofins Ntd Llc (ga) RCV000723622 SCV000231476 pathogenic not provided 2016-11-29 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000723622 SCV000961578 likely pathogenic not provided 2024-03-27 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. 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 ERCC6 are known to be pathogenic (PMID: 18628313, 29572252). This variant is present in population databases (rs371739894, gnomAD 0.003%). Disruption of this splice site has been observed in individual(s) with clinical features of ERCC6-related conditions (PMID: 29572252, 34052969). 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. 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 2023-04-12 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 canonical 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 (gnomAD). c.1526+1G>T has been reported in the literature in a compound heterozygous individual affected with Cockayne Syndrome (Calmels_2018) and in two individuals diagnosed with an unspecified primary mitochondrial disorder presenting with ataxia (Martin-Saavedra_2022). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=3)/likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Revvity Omics, Revvity RCV000723622 SCV002022207 pathogenic not provided 2019-05-02 criteria provided, single submitter clinical testing
GeneDx RCV000723622 SCV003798662 pathogenic not provided 2023-02-02 criteria provided, single submitter clinical testing Canonical splice site variant with an unclear effect on protein function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29572252, 34052969)
Fulgent Genetics, Fulgent Genetics RCV005042364 SCV005675159 likely pathogenic DE SANCTIS-CACCHIONE SYNDROME; Cerebrooculofacioskeletal syndrome 1; Cockayne syndrome type 2; UV-sensitive syndrome 1; Age related macular degeneration 5; Premature ovarian failure 11; Lung cancer 2024-04-30 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV005361058 SCV005917862 pathogenic Cockayne spectrum with or without cerebrooculofacioskeletal syndrome 2022-07-04 criteria provided, single submitter research
Counsyl RCV000983983 SCV000790451 likely pathogenic DE SANCTIS-CACCHIONE SYNDROME 2019-06-24 no assertion criteria provided clinical testing

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