Submissions for variant NM_000123.3(ERCC5):c.1789G>C (p.Val597Leu) (rs4150319)

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000625478	SCV000745529	likely benign	Xeroderma pigmentosum, group G	2015-09-21	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000625478	SCV000745991	likely benign	Xeroderma pigmentosum, group G	2016-04-29	criteria provided, single submitter	clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000995081	SCV001149076	likely benign	not provided	2016-08-01	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000625478	SCV001268024	uncertain significance	Xeroderma pigmentosum, group G	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Invitae	RCV000995081	SCV001416378	uncertain significance	not provided	2019-02-26	criteria provided, single submitter	clinical testing	This sequence change replaces valine with leucine at codon 597 of the ERCC5 protein (p.Val597Leu). The valine residue is weakly conserved and there is a small physicochemical difference between valine and leucine. This variant is present in population databases (rs4150319, ExAC 0.2%). This variant has not been reported in the literature in individuals with ERCC5-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Baylor Genetics	RCV001292856	SCV001481536	uncertain significance	Cerebrooculofacioskeletal syndrome 3	2019-09-25	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
ITMI	RCV000120868	SCV000085036	not provided	not specified	2013-09-19	no assertion provided	reference population
Department of Pathology and Laboratory Medicine,Sinai Health System	RCV000995081	SCV001550118	likely benign	not provided		no assertion criteria provided	clinical testing	The ERCC5 p.Val597Leu variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs4150319), ClinVar (classified as likely benign by DNA and Cytogenetics Diagnostics Unit, Erasmus Medical Center and Genome Diagnostics Laboratory, VU University Medical Center Amsterdam), and LOVD 3.0. The variant was identified in control databases in 348 of 268224 chromosomes at a frequency of 0.001297 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 285 of 118064 chromosomes (freq: 0.002414), European (Finnish) in 30 of 25106 chromosomes (freq: 0.001195), Other in 6 of 6702 chromosomes (freq: 0.000895), Latino in 22 of 35104 chromosomes (freq: 0.000627), African in 4 of 23616 chromosomes (freq: 0.000169) and South Asian in 1 of 30526 chromosomes (freq: 0.000033), but was not observed in the Ashkenazi Jewish or East Asian populations. The p.Val597 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.