Submissions for variant NM_000082.4(ERCC8):c.37G>T (p.Glu13Ter)

gnomAD frequency: 0.00005  dbSNP: rs121434324

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Myriad Genetics, Inc.	RCV000001786	SCV001194153	pathogenic	Cockayne syndrome type 1	2020-01-06	criteria provided, single submitter	clinical testing	NM_000082.3(ERCC8):c.37G>T(E13*) is classified as pathogenic in the context of ERCC8-related disorders. Sources cited for classification include the following: PMID 19894250 and 14661080. Classification of NM_000082.3(ERCC8):c.37G>T(E13*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001064361	SCV001229258	pathogenic	not provided	2024-10-15	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu13*) in the ERCC8 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ERCC8 are known to be pathogenic (PMID: 29572252). This variant is present in population databases (rs121434324, gnomAD 0.1%). This premature translational stop signal has been observed in individuals with Cockayne syndrome (PMID: 14661080, 29572252). ClinVar contains an entry for this variant (Variation ID: 1716). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001280547	SCV001467735	pathogenic	Cockayne syndrome	2020-12-23	criteria provided, single submitter	clinical testing	Variant summary: ERCC8 c.37G>T (p.Glu13X) 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 7.6e-05 in 251494 control chromosomes (gnomAD). c.37G>T has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Cockayne Syndrome (Cao_2004, Ridley_2005, Nardo_2009, Calmels_2018). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated the lack of protein product and greatly decreased cell survival after UV irradiation in patient derived fibroblasts (Ridley_2005, Nardo_2009). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and both of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000001786	SCV001653118	pathogenic	Cockayne syndrome type 1	2020-07-03	criteria provided, single submitter	clinical testing	The p.Glu13X variant in ERCC8 has been reported in 2 compound heterozygous and 3 homozgyous individuals with Cockayne syndrome (Cao 2004 PMID:14661080, Laugel 2010 PMID: 19894250, Calmels 2018 PMID: 29572252). It has been identified in 0.139% (14/10080) of Ashkenazi Jewish chromosomes and 0.004% of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). It is also reported in ClinVar (Variation ID: 1716). This nonsense variant leads to a premature termination codon at position 13, which is predicted to lead to a truncated or absent protein. Loss of function of the ERCC8 gene is an established disease mechanism in autosomal recessive Cockayne syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Cockayne syndrome. ACMG/AMP Criteria applied: PVS1_Strong, PM3_Strong.
GeneDx	RCV001064361	SCV001770831	pathogenic	not provided	2022-01-20	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: 25333069, 29572252, 29742419, 14661080, 15744458, 19894250)
Revvity Omics, Revvity	RCV001064361	SCV002024510	likely pathogenic	not provided	2021-03-30	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002490294	SCV002803534	pathogenic	Cockayne syndrome type 1; UV-sensitive syndrome 2	2024-05-08	criteria provided, single submitter	clinical testing
OMIM	RCV000001786	SCV000021942	pathogenic	Cockayne syndrome type 1	2004-01-01	no assertion criteria provided	literature only