Submissions for variant NM_005236.3(ERCC4):c.1853G>A (p.Arg618His)

gnomAD frequency: 0.00007  dbSNP: rs760922582

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV001819576	SCV002072324	uncertain significance	not specified	2019-03-28	criteria provided, single submitter	clinical testing
Invitae	RCV001869700	SCV002193969	uncertain significance	Xeroderma pigmentosum, group F; Cockayne syndrome; Fanconi anemia complementation group Q	2023-11-04	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 618 of the ERCC4 protein (p.Arg618His). This variant is present in population databases (rs760922582, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with ERCC4-related conditions. ClinVar contains an entry for this variant (Variation ID: 1337090). 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 with a positive predictive value of 80%. 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.
CeGaT Center for Human Genetics Tuebingen	RCV002074315	SCV002497888	uncertain significance	not provided	2022-02-01	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002471168	SCV002767622	uncertain significance	Fanconi anemia complementation group Q	2020-05-25	criteria provided, single submitter	clinical testing	A heterozygous missense variant was identified, NM_005236.2(ERCC4):c.1853G>A in exon 9 of 11 of the ERCC4 gene. This substitution is predicted to create a minor amino acid change from arginine to histidine at position 618 of the protein, NP_005227.1(ERCC4):p.(Arg618His). The arginine at this position has high conservation (100 vertebrates, UCSC), but is not situated in a known functional domain. In silico software predicts this variant to be disease causing (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD population database at a frequency of 0.007% (18 heterozygotes, 0 homozygotes). Two alternative residue changes at the same location has been reported in the gnomAD database at a frequency of 0.001% and 0.01%, respectively. This variant has not been previously reported in clinical cases. Based on information available at the time of curation, this variant has been classified as a VARIANT of UNCERTAIN SIGNIFICANCE (VUS).
Ambry Genetics	RCV002542582	SCV003543632	uncertain significance	Inborn genetic diseases	2022-01-28	criteria provided, single submitter	clinical testing	The c.1853G>A (p.R618H) alteration is located in exon 9 (coding exon 9) of the ERCC4 gene. This alteration results from a G to A substitution at nucleotide position 1853, causing the arginine (R) at amino acid position 618 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.