Submissions for variant NM_005236.3(ERCC4):c.2677A>G (p.Asn893Asp)

gnomAD frequency: 0.00036  dbSNP: rs201926295

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000702604	SCV000831463	uncertain significance	Xeroderma pigmentosum, group F; Cockayne syndrome; Fanconi anemia complementation group Q	2022-10-05	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 893 of the ERCC4 protein (p.Asn893Asp). This variant is present in population databases (rs201926295, gnomAD 0.05%). 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: 579347). 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 not expected to disrupt ERCC4 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
Mendelics	RCV000989537	SCV001139957	uncertain significance	Xeroderma pigmentosum, group F	2019-05-28	criteria provided, single submitter	clinical testing
GeneDx	RCV001785705	SCV002027974	uncertain significance	not provided	2021-05-21	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Genetic Services Laboratory, University of Chicago	RCV001816729	SCV002069958	uncertain significance	not specified	2021-05-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV002259009	SCV002537953	uncertain significance	Xeroderma pigmentosum	2021-06-28	criteria provided, single submitter	curation
Ambry Genetics	RCV002536360	SCV003697269	uncertain significance	Inborn genetic diseases	2022-05-11	criteria provided, single submitter	clinical testing	The c.2677A>G (p.N893D) alteration is located in coding exon 11 of the ERCC4 gene. This alteration results from a A to G substitution at nucleotide position 2677, causing the asparagine (N) at amino acid position 893 to be replaced by an aspartic acid (D). Based on data from the Genome Aggregation Database (gnomAD) database, the ERCC4 c.2677A>G alteration was observed in 0.03% (74/282652) of total alleles studied, with a frequency of 0.05% (62/129044) in the European (non-Finnish) subpopulation. This amino acid position is well conserved in available vertebrate species. The p.N893D alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000989537	SCV004031160	uncertain significance	Xeroderma pigmentosum, group F	2023-08-30	criteria provided, single submitter	clinical testing	The ERCC4 c.2677A>G (p.Asn893Asp) missense change has a maximum subpopulation frequency of 0.048% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but this prediction has not been confirmed by functional studies. This variant has not been reported in individuals with Fanconi anemia or xeroderma pigmentosum. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.