Submissions for variant NM_000124.4(ERCC6):c.2143G>T (p.Gly715Ter)

gnomAD frequency: 0.00001  dbSNP: rs780538788

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001061824	SCV001226583	pathogenic	not provided	2023-10-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gly715*) 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 (rs780538788, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with Cockayne Syndrome (PMID: 19894250, 29572252). ClinVar contains an entry for this variant (Variation ID: 856377). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002469337	SCV002765916	pathogenic	Cockayne syndrome	2022-11-17	criteria provided, single submitter	clinical testing	Variant summary: ERCC6 c.2143G>T (p.Gly715X) 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 by our laboratory. The variant allele was found at a frequency of 2.4e-05 in 251338 control chromosomes (gnomAD). c.2143G>T has been reported in the literature as a biallelic genotype in individuals affected with Cockayne Syndrome (e.g. Laugel_2010, Tonduti_2018, Calmels_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted a clinical-significance assessment for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV003339450	SCV004047457	pathogenic	Cockayne syndrome type 2		criteria provided, single submitter	clinical testing	The stop gained c.2143G>T (p.Gly715Ter) variant has been observed in individuals affected with Cockayne Syndrome (Laugel V et al., 2010). The p.Gly715Ter variant has allele frequency 0.0025% in gnomAD exomes and novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. The nucleotide change c.2143G>T in ERCC6 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.