Submissions for variant NM_000124.4(ERCC6):c.1669C>G (p.Arg557Gly)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002663212	SCV002985201	uncertain significance	not provided	2021-05-12	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with glycine at codon 557 of the ERCC6 protein (p.Arg557Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ERCC6-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004786732	SCV005399168	uncertain significance	Cockayne syndrome type 2	2020-05-25	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v0.6.1, this variant is classified as 3B-VUS. Following criteria are met: 0102 - Loss of function is a known mechanism of disease for this gene. 0108 - This gene is known to be associated with both recessive and dominant disease. 0200 - Variant is predicted to result in a missense amino acid change from arginine to glycine (exon 7). 0301 - Variant is absent from gnomAD. 0309 - Alternative amino acid changes at the same position have been observed in gnomAD (p.(Arg557His): 52 heterozygotes, 0 homozygotes; p.(Arg557Cys): 12 heterozygotes, 0 homozygotes). 0501 - Missense variant consistently predicted to be damaging by in silico tools or highly conserved with a major amino acid change. 0600 - Variant is located in an annotated domain or motif that does not have a well established function (helicase ATP-binding motif; PDB). 0705 - No comparable variants in relevant codon/region have previous evidence for pathogenicity. 0807 - Variant has not previously been reported in a clinical context. It has previously been described as variant of uncertain significance (LOVD). 0905 - No published segregation evidence has been identified for this variant. 1007 - No published functional evidence has been identified for this variant.