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

gnomAD frequency: 0.00005  dbSNP: rs121917901

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Claritas Genomics	RCV000001769	SCV000222794	pathogenic	Cockayne syndrome type 2	2012-01-09	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000406377	SCV000362890	pathogenic	ERCC6-related disorder	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.
Genetic Services Laboratory, University of Chicago	RCV000001769	SCV000594582	pathogenic	Cockayne syndrome type 2	2016-02-29	criteria provided, single submitter	clinical testing
GeneDx	RCV000521977	SCV000617667	pathogenic	not provided	2022-06-17	criteria provided, single submitter	clinical testing	Nonsense 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; This variant is associated with the following publications: (PMID: 25525159, 9443879, 28687971, 30111349, 32257569, 31589614)
Fulgent Genetics, Fulgent Genetics	RCV002476910	SCV000893161	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	2024-03-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000521977	SCV000937297	pathogenic	not provided	2025-01-21	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. Loss-of-function variants in ERCC6 are known to be pathogenic (PMID: 18628313, 29572252). This variant is present in population databases (rs121917901, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with Cockayne syndrome (PMID: 9443879). ClinVar contains an entry for this variant (Variation ID: 1701). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001199022	SCV001370017	pathogenic	Cerebrooculofacioskeletal syndrome 1	2019-02-11	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP5.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000521977	SCV001474159	pathogenic	not provided	2020-04-07	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000521977	SCV001714947	pathogenic	not provided	2019-11-03	criteria provided, single submitter	clinical testing	PVS1, PS3, PS4_moderate, PM2, PM3, PP4
Revvity Omics, Revvity	RCV000521977	SCV002022208	pathogenic	not provided	2021-04-08	criteria provided, single submitter	clinical testing
DECIPHERD-UDD, Universidad del Desarrollo	RCV000001769	SCV004171011	pathogenic	Cockayne syndrome type 2	2023-07-01	criteria provided, single submitter	research
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000001769	SCV005399460	pathogenic	Cockayne syndrome type 2	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with cerebrooculofacioskeletal syndrome 1 (MIM#214150), Cockayne syndrome, type B (MIM#133540), De Sanctis-Cacchione syndrome (MIM#278800), premature ovarian failure 11 (MIM#616946) and UV-sensitive syndrome 1 (MIM#600630). (I) 0108 - This gene is associated with both recessive and dominant disease. There is currently no clear genotype-phenotype correlation distinguishing between the autosomal recessive syndromes and autosomal dominant premature ovarian failure 11 (MIM#616946). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2: 24 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER, ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in several homozygous and compound heterozygous individuals with Cockayne syndrome, type B (MIM#133540; DECIPHER, ClinVar, PMID: 29572252). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000001769	SCV000021925	pathogenic	Cockayne syndrome type 2	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
Counsyl	RCV000001770	SCV000790360	pathogenic	DE SANCTIS-CACCHIONE SYNDROME	2017-03-16	no assertion criteria provided	clinical testing
Genomics England Pilot Project, Genomics England	RCV000001769	SCV001760252	likely pathogenic	Cockayne syndrome type 2		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000521977	SCV001954277	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000521977	SCV001976212	pathogenic	not provided		no assertion criteria provided	clinical testing