ClinVar Miner

Submissions for variant NM_000124.4(ERCC6):c.4015T>C (p.Phe1339Leu)

gnomAD frequency: 0.00003  dbSNP: rs116715649
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002023701 SCV002302519 uncertain significance not provided 2022-11-03 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1339 of the ERCC6 protein (p.Phe1339Leu). This variant is present in population databases (rs116715649, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with ERCC6-related conditions. ClinVar contains an entry for this variant (Variation ID: 1516113). 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, which suggests that this missense change does not adversely affect protein function. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002271716 SCV002555617 uncertain significance not specified 2022-06-01 criteria provided, single submitter clinical testing Variant summary: ERCC6 c.4015T>C (p.Phe1339Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251182 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ERCC6 causing Cockayne Syndrome (4e-05 vs 0.0016), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.4015T>C in individuals affected with Cockayne Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics RCV002498059 SCV002812132 uncertain significance DE SANCTIS-CACCHIONE SYNDROME; Cerebrooculofacioskeletal syndrome 1; Cockayne syndrome type 2; UV-sensitive syndrome 1; Age related macular degeneration 5; Premature ovarian failure 11; Lung cancer 2021-07-03 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV002023701 SCV003833594 uncertain significance not provided 2022-12-13 criteria provided, single submitter clinical testing
Breakthrough Genomics, Breakthrough Genomics RCV002023701 SCV005190732 uncertain significance not provided criteria provided, single submitter not provided

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