ClinVar Miner

Submissions for variant NM_005236.2(ERCC4):c.1563C>G (p.Ser521Arg) (rs41552412)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,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 2020-11-10 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].
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.

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