ClinVar Miner

Submissions for variant NM_005236.3(ERCC4):c.256C>T (p.Arg86Cys)

gnomAD frequency: 0.00002  dbSNP: rs769932063
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV001355944 SCV002009696 uncertain significance not provided 2021-11-03 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV003771041 SCV004573135 uncertain significance Xeroderma pigmentosum, group F; Cockayne syndrome; Fanconi anemia complementation group Q 2023-07-19 criteria provided, single submitter clinical testing Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ERCC4 protein function. ClinVar contains an entry for this variant (Variation ID: 1049608). This variant has not been reported in the literature in individuals affected with ERCC4-related conditions. This variant is present in population databases (rs769932063, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 86 of the ERCC4 protein (p.Arg86Cys). 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.
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001355944 SCV001550974 uncertain significance not provided no assertion criteria provided clinical testing The ERCC4 p.Arg86Cys variant was not identified in the literature nor was it identified in ClinVar, Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs769932063) and in control databases in 9 of 251278 chromosomes at a frequency of 0.00003582 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: East Asian in 2 of 18394 chromosomes (freq: 0.000109), South Asian in 2 of 30580 chromosomes (freq: 0.000065), African in 1 of 16252 chromosomes (freq: 0.000062) and European (non-Finnish) in 4 of 113652 chromosomes (freq: 0.000035), but was not observed in the Latino, Ashkenazi Jewish, European (Finnish), or Other populations. The p.Arg86 residue is not 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.

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