Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| 3billion | RCV001775082 | SCV002011916 | uncertain significance | Cerebrooculofacioskeletal syndrome 2 | 2024-07-30 | criteria provided, single submitter | clinical testing | The variant is observed at an extremely low frequency in the gnomAD v4.0.0 dataset (total allele frequency: 0.004%). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.67 (>=0.6); 3Cnet: 0.71 (>=0.6)]. The same nucleotide change resulting in the same amino acid change has been previously reported to be associated with ERCC2-related disorder (ClinVar ID: VCV000134093 / 3billion dataset). Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline. |
| Labcorp Genetics |
RCV001356923 | SCV002214630 | uncertain significance | not provided | 2022-08-23 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 497 of the ERCC2 protein (p.Arg497Cys). This variant is present in population databases (rs199738290, gnomAD 0.02%). 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: 134093). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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. |
| ITMI | RCV000120765 | SCV000084929 | not provided | not specified | 2013-09-19 | no assertion provided | reference population | |
| Department of Pathology and Laboratory Medicine, |
RCV001356923 | SCV001552216 | uncertain significance | not provided | no assertion criteria provided | clinical testing | The ERCC2 p.Arg497Cys variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs199738290) and ClinVar (classification not provided, submitted by ITMI). The variant was identified in control databases in 11 of 25143000 chromosomes at a frequency of 0.00004375 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: East Asian in 3 of 18392 chromosomes (freq: 0.000163), Latino in 4 of 34590 chromosomes (freq: 0.000116) and European (non-Finnish) in 4 of 113746 chromosomes (freq: 0.000035), but was not observed in the African, Ashkenazi Jewish, European (Finnish), Other and South Asian populations. The p.Arg497 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. |