Submissions for variant NM_000124.4(ERCC6):c.526C>T (p.Arg176Ter)

gnomAD frequency: 0.00003  dbSNP: rs771781694

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000666614	SCV000790933	likely pathogenic	DE SANCTIS-CACCHIONE SYNDROME; Cerebrooculofacioskeletal syndrome 1; Cockayne syndrome type 2	2017-04-14	criteria provided, single submitter	clinical testing
GeneDx	RCV001731863	SCV001982610	pathogenic	not provided	2021-10-05	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: 24700531, 25356239)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001731863	SCV002233557	pathogenic	not provided	2024-10-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg176*) 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 (rs771781694, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with clinical features of Cockayne syndrome (PMID: 25356239, 29572252). ClinVar contains an entry for this variant (Variation ID: 551532). 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.
Neuberg Centre For Genomic Medicine, NCGM	RCV003338726	SCV004048300	pathogenic	Cockayne syndrome type 2		criteria provided, single submitter	clinical testing	The stop gained variant c.526C>T (p.Arg176Ter) in ERCC6 gene has been reported previously in homozygous state in patients affected with Cockayne syndrome (Luo et al., 2014). The p.Arg176Ter variant is reported with the allele frequency (0.002%) in the gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. It has been submitted to ClinVar with varying interpretations: Pathogenic/ Likely Pathogenic. The nucleotide change 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
Ambry Genetics	RCV003352980	SCV004077687	pathogenic	Inborn genetic diseases	2023-07-17	criteria provided, single submitter	clinical testing	The c.526C>T (p.R176*) alteration, located in exon 3 (coding exon 2) of the ERCC6 gene, consists of a C to T substitution at nucleotide position 526. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 176. 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 0.003% (8/282646) total alleles studied. The highest observed frequency was 0.01% (3/30604) of South Asian alleles. This variant has been reported to be homozygous or compound heterozygous in multiple individuals with features consistent with ERCC6-related disorders (Luo, 2014; Calmels, 2018). Based on the available evidence, this alteration is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004800516	SCV005422954	pathogenic	Cockayne syndrome	2024-10-08	criteria provided, single submitter	clinical testing	Variant summary: ERCC6 c.526C>T (p.Arg176X) 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. The variant allele was found at a frequency of 2.8e-05 in 251268 control chromosomes. c.526C>T has been reported in the literature in the homozyougs and compound heterozygous state in individuals affected with Cockayne Syndrome (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. The following publication have been ascertained in the context of this evaluation (PMID: 29572252). ClinVar contains an entry for this variant (Variation ID: 551532). Based on the evidence outlined above, the variant was classified as pathogenic.