Variant summary: ERCC6 c.3952_3953delAG (p.Arg1318GlyfsX12) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic in ClinVar database. The variant allele was found at a frequency of 2e-05 in 251212 control chromosomes (gnomAD). c.3952_3953delAG has been reported in the literature in two individuals affected with Cockayne Syndrome (Calmels_2018), one individual with clinical diagnosis and family history of hearing loss, loss of ambulation, hypotonia, cerebellar ataxia and sensory neuropathy (Monies_2019), one individual affected with acute lymphoblastic leukemia (Qin_2020) and one individual affected with malignant peritoneal mesothelioma (Hung_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=2) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Reported in two unrelated patients with Cockayne syndrome who each harbored another variant in the ERCC6 gene (PMID: 29572252); Identified in a patient with a clinical diagnosis and family history of hearing loss, loss of ambulation, hypotonia, cerebellar ataxia and sensory neuropathy who underwent exome sequencing; this individual also harbored an intronic variant in ERCC6 though its clinical significance was considered to be unknown (PMID: 31130284); This variant is associated with the following publications: (PMID: 18628313, 9443879, 31130284, 29572252)

The c.3952_3953delAG (p.R1318Gfs) variant is a frameshift deletion of two nucleotides predicted to result in a nonfunctional ERCC6 protein.

This sequence change creates a premature translational stop signal (p.Arg1318Glyfs*12) in the ERCC6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ERCC6 are known to be pathogenic (PMID: 18628313, 29572252). This variant is present in population databases (rs765825423, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with Cockayne syndrome type B (PMID: 29572252). ClinVar contains an entry for this variant (Variation ID: 190171). For these reasons, this variant has been classified as Pathogenic.

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.