ClinVar Miner

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

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Total submissions: 8
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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.

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