Submissions for variant NM_000124.4(ERCC6):c.2203C>T (p.Arg735Ter) (rs121917901)

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Claritas Genomics	RCV000001769	SCV000222794	pathogenic	Cockayne syndrome B	2012-01-09	criteria provided, single submitter	clinical testing
Counsyl	RCV000666117	SCV000790360	pathogenic	DE SANCTIS-CACCHIONE SYNDROME; Cerebro-oculo-facio-skeletal syndrome; Cockayne syndrome B	2017-03-16	criteria provided, single submitter	clinical testing
Fulgent Genetics,Fulgent Genetics	RCV000762810	SCV000893161	pathogenic	DE SANCTIS-CACCHIONE SYNDROME; Cerebro-oculo-facio-skeletal syndrome; Cockayne syndrome B; Lung cancer; UV-sensitive syndrome; Age-related macular degeneration 5; Premature ovarian failure 11	2018-10-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000521977	SCV000617667	pathogenic	not provided	2018-01-23	criteria provided, single submitter	clinical testing	The R735X variant in the ERCC6 gene has been reported previously in association with Cockayne syndrome, when present in the homozygous state or heterozygous with another disease-causing variant (Mallery et al., 1998). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R735X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret R735X as a pathogenic variant.
Genetic Services Laboratory, University of Chicago	RCV000001769	SCV000594582	pathogenic	Cockayne syndrome B	2016-02-29	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000406377	SCV000362890	pathogenic	ERCC6-Related Disorders	2017-04-28	criteria provided, single submitter	clinical testing	The ERCC6 c.2203C>T (p.Arg735Ter) variant is a stop-gained variant predicted to result in permature termination of the protein. The p.Arg735Ter variant has been reported in at least three studies in which it is found in a total of five patients, including one homozygote and two compound heterozygotes with Cockayne syndrome, and two homozygotes with de Sanctis-Cacchione syndrome (Mallery et al. 1998; Colella et al. 2000; Laugel et al. 2010). Control data are unavailable for this variant which is reported at a frequency of 0.00015 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies using primary fibroblast cell lines derived from patients with the p.Arg735Ter variant showed that the variant was associated with defective telomere maintenance as well as increased reactive oxygen species and mitochondrial oxidative stress but was not associated with nuclear DNA damage (Batenburg et al. 2012; Cleaver et al. 2014). Functional studies of induced pluripotent stem cells derived from skin fibroblasts carrying the p.Arg735Ter variant also showed that the lack of functional CSB protein caused by the variant did not prevent genetic reprogramming but did increase cell death and reactive oxygen species production (Andrade et al. 2012). Further, in a telomerase-immortalized cell line carrying the p.Arg375Ter variant in a homozygous state, addition of wild type CSB showed a significant decrease in the amount of cells with IR-induced 53BP1 foci and a significantly increased amount of cells with cyclin A and IR-induced foci of BRCA1, RPA, and Rad51, suggesting there is defective homologous recombination-mediated double strand break repair (Batenburg et al. 2015). Based on the collective evidence and the potential impact of stop-gained variants, the p.Arg275Ter variant is classified as pathogenic for ERCC6-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV000521977	SCV000937297	pathogenic	not provided	2018-10-12	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg735*) in the ERCC6 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs121917901, ExAC 0.01%). This variant has been observed in individuals affected with Cockayne syndrome (PMID: 9443879). ClinVar contains an entry for this variant (Variation ID: 1701). Loss-of-function variants in ERCC6 are known to be pathogenic (PMID: 9443879, 18628313). For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000001769	SCV000021925	pathogenic	Cockayne syndrome B	2000-05-01	no assertion criteria provided	literature only
OMIM	RCV000001770	SCV000021926	pathogenic	DE SANCTIS-CACCHIONE SYNDROME	2000-05-01	no assertion criteria provided	literature only