Submissions for variant NM_001983.4(ERCC1):c.466C>T (p.Arg156Trp)

gnomAD frequency: 0.00007  dbSNP: rs757369063

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001257143	SCV001432711	pathogenic	Failure to thrive; Cutaneous photosensitivity; Cholestatic liver disease; Premature ovarian insufficiency; Global proximal tubulopathy	2018-09-10	criteria provided, single submitter	clinical testing	A hemizygous missense variant, NM_202001.2(ERCC1):c.466C>T, has been identified in exon 4 of 8 of the ERCC1 gene. The variant is predicted to result in a major amino acid change from arginine to tryptophan at position 156 of the protein, NP_973730.1(ERCC1):p.(Arg156Trp). The arginine residue at this position has very high conservation (100 vertebrates, UCSC), and is located within the RAD10 superfamily functional domain. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD database at a frequency of 0.01% (22 heterozygotes). This variant has not been previously reported in clinical cases. Functional studies have demonstrated very low levels of ERCC1 recruitment to UV-damaged patient cells and a defect in nucleotide excision repair in this patient's cell line. Based on the information available at the time of curation and in conjunction with the deletion of exon 4, this variant has been classified as PATHOGENIC.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV001806093	SCV002051631	likely pathogenic	not provided	2021-03-11	criteria provided, single submitter	clinical testing	PS3, PP3, PM2, PM3
GeneDx	RCV001806093	SCV002319038	pathogenic	not provided	2022-10-13	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect with significantly reduced protein levels of ERCC1 (Apelt et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33315086)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001806093	SCV003461451	uncertain significance	not provided	2022-02-21	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 156 of the ERCC1 protein (p.Arg156Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with Cockayne and cerebrooculofacioskeletal syndrome (PMID: 33315086). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 978472). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects ERCC1 function (PMID: 33315086). 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.