ClinVar Miner

Submissions for variant NM_000400.4(ERCC2):c.2189G>A (p.Arg730Gln)

dbSNP: rs759412116
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001573853 SCV002206459 uncertain significance not provided 2022-08-16 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 730 of the ERCC2 protein (p.Arg730Gln). This variant is present in population databases (rs759412116, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with ERCC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1206329). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Sema4, Sema4 RCV002255682 SCV002531591 uncertain significance Xeroderma pigmentosum 2021-11-29 criteria provided, single submitter curation
Ambry Genetics RCV002424994 SCV002730619 uncertain significance Inborn genetic diseases 2023-06-06 criteria provided, single submitter clinical testing The c.2189G>A (p.R730Q) alteration is located in exon 22 (coding exon 22) of the ERCC2 gene. This alteration results from a G to A substitution at nucleotide position 2189, causing the arginine (R) at amino acid position 730 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004587185 SCV005077276 uncertain significance not specified 2024-04-18 criteria provided, single submitter clinical testing Variant summary: ERCC2 c.2189G>A (p.Arg730Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 6e-05 in 250376 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ERCC2 causing Xeroderma Pigmentosum (6e-05 vs 0.00061), allowing no conclusion about variant significance. c.2189G>A has been reported in the literature as a compound heterozygous genotype in a 4 month old male, Microcephaly, global developmental delay, growth retardation, simian line, skin rash, anemia, neonatal sepsis, reporting an OMIM disease as Cerebrooculofacioskeletal syndrome 2 (example, Wang_2023). These authors reported a Likely Pathogenic outcome citing ACMG criteria PM2+PP3+PM3. 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: 37501076). ClinVar contains an entry for this variant (Variation ID: 1206329). Since the relationship of this phenotype to ERCC2 gene is considered provisional at the time of this ascertainment (OMIM), based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV001573853 SCV001800300 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV001573853 SCV001974781 likely benign not provided no assertion criteria provided clinical testing

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