Submissions for variant NM_000082.4(ERCC8):c.1012G>A (p.Asp338Asn)

gnomAD frequency: 0.00063  dbSNP: rs141845482

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000658089	SCV000779860	uncertain significance	not provided	2018-05-17	criteria provided, single submitter	clinical testing	The D338N variant in the ERCC8 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. Although not observed in the homozygous state, the D338N variant is observed in 101/126354 (0.080%) alleles from individuals of non-Finnish European background and 113/276718 (0.041%) total alleles in large population cohorts (Lek et al., 2016). The D338N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. We interpret D338N as a variant of uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV000764612	SCV000895711	uncertain significance	Cockayne syndrome type 1; UV-sensitive syndrome 2	2022-03-18	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001152254	SCV001313466	uncertain significance	Cockayne syndrome type 1	2018-03-16	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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000658089	SCV001713320	uncertain significance	not provided	2022-10-26	criteria provided, single submitter	clinical testing	BP4
Labcorp Genetics (formerly Invitae), Labcorp	RCV000658089	SCV002949031	uncertain significance	not provided	2024-10-08	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 338 of the ERCC8 protein (p.Asp338Asn). This variant is present in population databases (rs141845482, gnomAD 0.08%). This variant has not been reported in the literature in individuals affected with ERCC8-related conditions. ClinVar contains an entry for this variant (Variation ID: 546240). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ERCC8 protein function with a negative 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	RCV000658089	SCV004162866	likely benign	not provided	2022-11-01	criteria provided, single submitter	clinical testing	ERCC8: BS1