ClinVar Miner

Submissions for variant NM_000124.4(ERCC6):c.1685+5G>A

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV003072456 SCV003467995 uncertain significance not provided 2022-04-12 criteria provided, single submitter clinical testing This sequence change falls in intron 7 of the ERCC6 gene. It does not directly change the encoded amino acid sequence of the ERCC6 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (no rsID available, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with ERCC6-related conditions. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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 available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV004594668 SCV005086510 likely pathogenic Cockayne syndrome type 2 2020-05-21 criteria provided, single submitter clinical testing The heterozygous splice variant, NM_000124.3(ERCC6):c.1685+5G>A, was identified in intron 7 of the ERCC6 gene (chr10:50708579).�This substitution is predicted to cause a loss of the canonical donor site of exon�7, which may result in a truncated protein; further tests are required to confirm this.�The nucleotide at this position has high conservation (100 vertebrates, UCSC).�This variant is present in population databases at a frequency of 0.0008% (ExAC, GnomAD) but has not been previously observed in our cohort or in other clinical cases. However, other splice site variants, including canonical and non canonical splice sites, have been reported as PATHOGENIC in patients with Cockayne syndrome (ClinVar). Based on current information, this variant has been classified as LIKELY PATHOGENIC.� The presence of these two variants suggests a possible compound heterozygous mode of inheritance which is consistent with Cockayne syndrome.

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