Total submissions: 12
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Illumina Laboratory Services, |
RCV000343662 | SCV000394872 | uncertain significance | Xeroderma pigmentosum, group F | 2018-01-12 | criteria provided, single submitter | clinical testing | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. |
Labcorp Genetics |
RCV000546465 | SCV000654057 | likely benign | Xeroderma pigmentosum, group F; Cockayne syndrome; Fanconi anemia complementation group Q | 2025-01-07 | criteria provided, single submitter | clinical testing | |
Fulgent Genetics, |
RCV000764023 | SCV000894976 | uncertain significance | Xeroderma pigmentosum, group F; XFE progeroid syndrome; Fanconi anemia complementation group Q | 2018-10-31 | criteria provided, single submitter | clinical testing | |
Baylor Genetics | RCV001292825 | SCV001481498 | uncertain significance | Fanconi anemia complementation group Q | 2019-04-13 | criteria provided, single submitter | clinical testing | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. |
Institute for Clinical Genetics, |
RCV001355143 | SCV002009712 | uncertain significance | not provided | 2021-11-03 | criteria provided, single submitter | clinical testing | |
Genetic Services Laboratory, |
RCV000120826 | SCV002071308 | uncertain significance | not specified | 2020-12-15 | criteria provided, single submitter | clinical testing | DNA sequence analysis of the ERCC4 gene demonstrated a sequence change, c.1563C>G, in exon 8 that results in an amino acid change, p.Ser521Arg. This sequence change does not appear to have been previously described in patients with ERCC4-related disorders and has been described in the gnomAD database with a relatively high population frequency of 0.11% in non-Finnish European subpopulations (dbSNP rs41552412). The p.Ser521Arg change affects a moderately conserved amino acid residue located in a domain of the ERCC4 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ser521Arg substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Ser521Arg change remains unknown at this time. |
Sema4, |
RCV002258801 | SCV002537728 | likely benign | Xeroderma pigmentosum | 2022-01-06 | criteria provided, single submitter | curation | |
Revvity Omics, |
RCV001355143 | SCV003833577 | uncertain significance | not provided | 2019-10-29 | criteria provided, single submitter | clinical testing | |
Ce |
RCV001355143 | SCV004141170 | likely benign | not provided | 2024-07-01 | criteria provided, single submitter | clinical testing | ENSG00000262732: BS2; ERCC4: BP4, BS2 |
ITMI | RCV000120826 | SCV000084991 | not provided | not specified | 2013-09-19 | no assertion provided | reference population | |
Department of Pathology and Laboratory Medicine, |
RCV001355143 | SCV001549937 | uncertain significance | not provided | no assertion criteria provided | clinical testing | The ERCC4 p.Ser521Arg variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs41552412) as "With Uncertain significance allele", LOVD 3.0, and in ClinVar (classified as a VUS by Illumina, Invitae, Fulgent Genetics and ITMI; associated conditions of Xeroderma pigmnetosum, XFE progeroid syndrome, Cockayne syndrome, and Fanconi anemia complementation group Q).The variant was also identified in control databases in 240 of 282606 chromosomes (1 homozygous) at a frequency of 0.000849 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 81 of 35434 chromosomes (freq: 0.002286), Other in 13 of 7214 chromosomes (freq: 0.001802), European (non-Finnish) in 140 of 129056 chromosomes (freq: 0.001085) and African in 6 of 24864 chromosomes (freq: 0.000241), while the variant was not observed in the Ashkenazi Jewish, East Asian, European (Finnish) and South Asian populations. Bodian et al. sequenced whole genomes from 681 healthy individuals; the p.S521R variant was identified at an allele frequency of 0.0015 in the European population, and was not found in any other population frequency within the cohort (Bodian_2014_PMID: 24728327). The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder-like & MaxEntScan) predict the gain of a 5' splice site at c.1562 and c.1558, respectively. The p.Ser521 residue is conserved in mammals but not distantly related organisms, 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. 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. | |
Prevention |
RCV003975071 | SCV004798399 | likely benign | ERCC4-related disorder | 2022-07-20 | no assertion criteria provided | clinical testing | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). |