Submissions for variant NM_020207.7(ERCC6L2):c.19C>T (p.Gln7Ter)

gnomAD frequency: 0.00031  dbSNP: rs778926161

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000480857	SCV000571324	likely pathogenic	not provided	2021-07-02	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; Not observed at significant frequency in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27535533)
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV001270090	SCV001448905	likely pathogenic	Pancytopenia-developmental delay syndrome	2019-12-13	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001270090	SCV002024508	likely pathogenic	Pancytopenia-developmental delay syndrome	2019-10-16	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000480857	SCV002242873	pathogenic	not provided	2025-02-03	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln18*) in the ERCC6L2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ERCC6L2 are known to be pathogenic (PMID: 24507776, 27185855, 29146883, 29987015). This variant is present in population databases (rs778926161, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with ERCC6L2-related conditions. ClinVar contains an entry for this variant (Variation ID: 421974). For these reasons, this variant has been classified as Pathogenic.
AiLife Diagnostics, AiLife Diagnostics	RCV000480857	SCV002502602	likely pathogenic	not provided	2022-03-22	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001270090	SCV005879479	likely pathogenic	Pancytopenia-developmental delay syndrome	2024-08-21	criteria provided, single submitter	clinical testing	The ERCC6L2 c.19C>T; p.Gln7Ter variant (rs778926161, ClinVar Variation ID: 421974) is reported in the literature in the homozygous state in an individual affected with myelodysplastic syndrome (Feurstein 2022). This variant is found in the general population with an overall allele frequency of 0.0048% (11/230600 alleles) in the Genome Aggregation Database (v2.1.1). This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be likely pathogenic. References: Feurstein S et al. Germ line predisposition variants occur in myelodysplastic syndrome patients of all ages. Blood. 2022 Dec 15;140(24):2533-2548. PMID: 35969835.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001270090	SCV005888057	pathogenic	Pancytopenia-developmental delay syndrome	2025-01-20	criteria provided, single submitter	clinical testing	Variant summary: ERCC6L2 c.19C>T (p.Gln7X) 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 5e-05 in 199200 control chromosomes (gnomAD). This frequency is not higher than estimated for a pathogenic variant in ERCC6L2 causing Pancytopenia-Developmental Delay Syndrome, allowing no conclusion about variant significance. The variant, c.19C>T (NM_020207.7), has been reported in the literature in homozygous- and compound heterozygous state in individuals affected with Pancytopenia-Developmental Delay Syndrome (e.g. Hakkarainen_2023, Feurstein_2023). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36952636, 37091189). ClinVar contains an entry for this variant (Variation ID: 421974). Based on the evidence outlined above, the variant was classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004751561	SCV005351045	pathogenic	ERCC6L2-related disorder	2024-06-14	no assertion criteria provided	clinical testing	The ERCC6L2 c.52C>T variant is predicted to result in premature protein termination (p.Gln18*). This variant, commonly referred to as p.Gln7*, was reported in the homozygous or compound heterozygous state in individuals with myelodysplastic syndrome (Feurstein et al. 2022. PubMed ID: 35969835; Hakkarainen et al. 2023. PubMed ID: 36952636). This variant is reported in 0.0089% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in ERCC6L2 are expected to be pathogenic. This variant is interpreted as pathogenic.