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

gnomAD frequency: 0.00002  dbSNP: rs769932063

Total submissions: 3

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
Invitae	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.