Submissions for variant NM_005236.3(ERCC4):c.1563C>G (p.Ser521Arg)

gnomAD frequency: 0.00099  dbSNP: rs41552412

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	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.
Invitae	RCV000546465	SCV000654057	likely benign	Xeroderma pigmentosum, group F; Cockayne syndrome; Fanconi anemia complementation group Q	2023-12-28	criteria provided, single submitter	clinical testing
Fulgent Genetics, 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, University Hospital TU Dresden, University Hospital TU Dresden	RCV001355143	SCV002009712	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	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, Sema4	RCV002258801	SCV002537728	likely benign	Xeroderma pigmentosum	2022-01-06	criteria provided, single submitter	curation
Revvity Omics, Revvity	RCV001355143	SCV003833577	uncertain significance	not provided	2019-10-29	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001355143	SCV004141170	likely benign	not provided	2023-09-01	criteria provided, single submitter	clinical testing	ERCC4: BP4, BS2
PreventionGenetics, part of Exact Sciences	RCV003975071	SCV004798399	likely benign	ERCC4-related disorder	2022-07-20	criteria provided, single submitter	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).
ITMI	RCV000120826	SCV000084991	not provided	not specified	2013-09-19	no assertion provided	reference population
Department of Pathology and Laboratory Medicine, Sinai Health System	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.