Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Illumina Laboratory Services, |
RCV000018045 | SCV000382117 | uncertain significance | Xeroderma pigmentosum, group G | 2017-04-27 | criteria provided, single submitter | clinical testing | The ERCC5 c.2620G>A (p.Ala874Thr) missense variant has been reported in a single study in which it was found in a compound heterozygous state with a stop-gained variant in one patient with a mild phenotype belonging to the xeroderma pigmentosum (XP) complementation group G (Emmert et al. 2002). The p.Ala874Thr variant was absent from 104 controls (Emmert et al. 2002) and is reported at a frequency of 0.00002 in the total population of the Exome Aggregation Consortium. Functional studies of the variant in patient fibroblasts showed a marked reduction in post-UV cell survival and DNA repair compared to wild type cells but nearly normal levels of mRNA expression. The variant protein was also shown to have residual ability to complement XP group G cells, consistent with the mild phenotype (Emmert et al. 2002). The p.Ala874Thr variant is located in the highly conserved I-region that is thought to be part of the active site of the enzyme. Based on the evidence, the p.Ala874Thr variant is considered to be of unknown significance but suspicious for pathogenicity for xeroderma pigmentosum. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001844013 | SCV002103343 | uncertain significance | not specified | 2022-02-23 | criteria provided, single submitter | clinical testing | Variant summary: ERCC5 c.2620G>A (p.Ala874Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251456 control chromosomes (gnomAD). c.2620G>A has been reported in the literature in a compound heterozygous individual who carried a truncating variant in trans, and was affected with a milder phenotype (i.e. sun sensitivity but no neurological abnormalities) of Xeroderma Pigmentosum (Emmert_2002). These data do not allow clear conclusions about variant significance. However, publications also reported experimental evidence evaluating an impact on protein function, and demonstrated markedly decreased but significant residual activity for the variant protein (Emmert_2002, Tsutakawa_2020), which is consistent with the milder phenotype. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as uncertain significance (but suspicious for pathogenicity). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |
| Ambry Genetics | RCV002513091 | SCV003615368 | uncertain significance | Inborn genetic diseases | 2022-05-02 | criteria provided, single submitter | clinical testing | The c.2620G>A (p.A874T) alteration is located in exon 12 (coding exon 12) of the ERCC5 gene. This alteration results from a G to A substitution at nucleotide position 2620, causing the alanine (A) at amino acid position 874 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. |
| OMIM | RCV000018045 | SCV000038324 | pathogenic | Xeroderma pigmentosum, group G | 2002-06-01 | no assertion criteria provided | literature only |