Submissions for variant NM_005236.3(ERCC4):c.1135C>T (p.Pro379Ser)

gnomAD frequency: 0.00471  dbSNP: rs1799802

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000120821	SCV000247313	benign	not specified	2021-03-24	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224511	SCV000281147	uncertain significance	not provided	2015-05-06	criteria provided, single submitter	clinical testing	Converted during submission to Uncertain significance.
Invitae	RCV001083882	SCV000288838	benign	Xeroderma pigmentosum, group F; Cockayne syndrome; Fanconi anemia complementation group Q	2024-01-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001116216	SCV001274263	likely benign	Xeroderma pigmentosum, group F	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000224511	SCV002009715	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000120821	SCV002500225	benign	not specified	2022-03-08	criteria provided, single submitter	clinical testing	Variant summary: ERCC4 c.1135C>T (p.Pro379Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.004 in 250774 control chromosomes in the gnomAD database, including 6 homozygotes. The observed variant frequency is approximately 20 fold of the estimated maximal expected allele frequency for a pathogenic variant in ERCC4 causing Xeroderma Pigmentosum phenotype (0.00019), strongly suggesting that the variant is benign. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as benign (n=2), likely benign (n=1) and VUS (n=2). Based on the evidence outlined above, the variant was classified as benign.
Sema4, Sema4	RCV002257432	SCV002537721	likely benign	Xeroderma pigmentosum	2020-11-11	criteria provided, single submitter	curation
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224157	SCV003919923	likely benign	Xeroderma pigmentosum, group F; XFE progeroid syndrome; Fanconi anemia complementation group Q	2022-08-23	criteria provided, single submitter	clinical testing	This variant has been reported in the literature in the compound heterozygous and homozygous states in at least 3 individuals with mild xeroderma pigmentosum (Ahmad 2010 PMID:20221251; Fassihi 2016 PMID:26884178). This variant is present in the Genome Aggregation Database (Highest reported MAF: 0.7% [463/67788], including in 7 total homozygotes; https://gnomad.broadinstitute.org/variant/16-13934224-C-T?dataset=gnomad_r3), and is present in ClinVar (Variation ID:134148). Evolutionary conservation and computational predictive tools for this variant are unclear. Functional studies have shown a mildly deleterious effect of this variant on some aspects of protein function, while minimal to no effect on other aspects (Ahmad 2010 PMID:20221251; Sabatella 2018 PMID:30165384). However, these studies may not accurately represent in vivo biological function. This variant may confer a slight increase in the risk for sunburn (OR: 1.31, 95% CI [1.257, 1.431]) (Backman 2021 PMID:34662886). In summary, data on this variant suggests that this variant does not cause disease but requires further evidence. Therefore, this variant is classified as likely benign.
CeGaT Center for Human Genetics Tuebingen	RCV000224511	SCV004010458	likely benign	not provided	2024-03-01	criteria provided, single submitter	clinical testing	ERCC4: BS2
PreventionGenetics, part of Exact Sciences	RCV003925183	SCV004741827	likely benign	ERCC4-related disorder	2019-04-25	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
ITMI	RCV000120821	SCV000084986	not provided	not specified	2013-09-19	no assertion provided	reference population