Submissions for variant NM_000124.4(ERCC6):c.2167C>T (p.Gln723Ter)

gnomAD frequency: 0.00009  dbSNP: rs151242354

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Claritas Genomics	RCV000170378	SCV000222793	pathogenic	Cockayne syndrome type 2	2013-01-07	criteria provided, single submitter	clinical testing
GeneDx	RCV000256036	SCV000321604	pathogenic	not provided	2022-08-04	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: 21228398, 19894250, 23311583, 25326635, 27356891, 29572252, 31980526)
Baylor Genetics	RCV000170378	SCV000807646	pathogenic	Cockayne syndrome type 2	2017-09-01	criteria provided, single submitter	clinical testing	This mutation has been previously reported as disease-causing and was found twice in our laboratory in trans with another pathogenic mutation in patients, including one with suspected diagnosis of Cockayne syndrome. Heterozygotes are expected to be asymptomatic carriers.
Illumina Laboratory Services, Illumina	RCV000778283	SCV000914459	pathogenic	ERCC6-Related Disorders	2018-12-10	criteria provided, single submitter	clinical testing	The ERCC6 c.2167C>T (p.Gln723Ter) variant is a stop-gained in the splice region variant that is predicted to result in premature truncation of the protein. The p.Gln723Ter variant has been reported in two studies in which it is found in a total of 12 individuals affected with Cockayne syndrome-B, including in two in a homozygous state and in ten in a compound heterozygous state with a unique null variant (Laugel et al. 2010; Calmels et al. 2018). Control data are unavailable for this variant, which is reported at a frequency of 0.00047 in the European American population of the Exome Sequencing Project. The p.Gln723Ter variant has not been reported in the literature in association with macular degeneration or cerebrooculofacioskeletal syndrome. Based on the collective evidence and the potential impact of stop-gained variants, the p.Gln723Ter 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	RCV000256036	SCV001233485	pathogenic	not provided	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln723*) 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 (rs151242354, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with Cockayne syndrome (PMID: 19894250). ClinVar contains an entry for this variant (Variation ID: 190160). 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.
Molecular Genetics, Royal Melbourne Hospital	RCV000170378	SCV002503804	pathogenic	Cockayne syndrome type 2	2022-04-22	criteria provided, single submitter	clinical testing	This sequence change is predicted to create a premature termination codon at position 723 in exon 10 (of 21) of ERCC6, p.(Gln723*). However, it has been demonstrated in RNA assays that this variant causes in-frame exon 10 skipping (p.Phe665_Gln723del) leading to the removal of the helical-like domain III, which the role of is not well-established (PMID: 29572252). The variant is present in a large population cohort at a frequency of 0.007%, which is consistent with a recessive condition (rs151242354, 20/282,734 alleles, 0 homozygotes in gnomAD v2.1). The variant has been identified as homozygous and compound heterozygous with a second pathogenic allele in multiple individuals with Cockayne syndrome spanning the full phenotype spectrum and mostly originating from the United Kingdom (PMID: 25326635, 29572252). Defective post-UV recovery of RNA synthesis has also been demonstrated in the cells of affected individuals (PMID: 29572252). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC . Following criteria are met: PM3_VeryStrong, PVS1_Moderate, PM2, PP4.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271443	SCV002555999	pathogenic	Cockayne syndrome	2022-06-20	criteria provided, single submitter	clinical testing	Variant summary: ERCC6 c.2167C>T (p.Gln723X) 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 (e.g. c.3862C>T (p.Arg1288X); c.2569C>T (p.Arg857X); ClinVar). The variant allele was found at a frequency of 6.4e-05 in 251352 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ERCC6 causing Cockayne Syndrome (6.4e-05 vs 0.0016). c.2167C>T has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Cockayne Syndrome and is seen primarily in individuals from the UK, suggesting a potential founder effect (e.g. Laugel_2010, Clamels_2018). These data indicate that the variant is very likely to be associated with disease. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Five laboratories classified the variant as pathogenic and one as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000170378	SCV002767664	pathogenic	Cockayne syndrome type 2	2020-05-21	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0108 - This gene is known to be associated with both recessive and dominant disease. However only recessive inheritance has been reported for Cockayne syndrome, type B (OMIM) (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (exon 10 of 21). (P) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (22 heterozygous, 0 homozygous). (P) 0701 - Comparable variants also predicted to result in NMD, have very strong previous evidence for pathogenicity for Cockayne syndrome (ClinVar, Decipher). (P) 0801 - Strong previous evidence of pathogenicity in multiple unrelated individuals with Cockayne syndrome (ClinVar, Decipher, Laugel, V. et al. (2010)) (P) 1206 - Variant is paternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Fulgent Genetics, Fulgent Genetics	RCV002505228	SCV002811060	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	2021-09-27	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000256036	SCV003830673	likely pathogenic	not provided	2022-10-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003352790	SCV004063648	pathogenic	Inborn genetic diseases	2023-07-17	criteria provided, single submitter	clinical testing	The c.2167C>T (p.Q723*) alteration, located in exon 10 (coding exon 9) of the ERCC6 gene, consists of a C to T substitution at nucleotide position 2167. This changes the amino acid from a glutamine (Q) to a stop codon at amino acid position 723. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the T allele has an overall frequency of 0.007% (20/282734) total alleles studied. The highest observed frequency was 0.013% (17/129108) of European (non-Finnish) alleles. This variant has been reported to be homozygous or compound heterozygous in multiple individuals with features consistent with ERCC6-related disorders (Laugel, 2010; Calmels, 2018). Based on the available evidence, this alteration is classified as pathogenic.
Counsyl	RCV000983999	SCV000792505	likely pathogenic	DE SANCTIS-CACCHIONE SYNDROME	2017-06-26	no assertion criteria provided	clinical testing
Genomics England Pilot Project, Genomics England	RCV000170378	SCV001760253	likely pathogenic	Cockayne syndrome type 2		no assertion criteria provided	clinical testing