ClinVar Miner

Submissions for variant NM_005236.3(ERCC4):c.1544G>A (p.Arg515His)

gnomAD frequency: 0.00001  dbSNP: rs766111215
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001871916 SCV002217745 uncertain significance Xeroderma pigmentosum, group F; Cockayne syndrome; Fanconi anemia complementation group Q 2021-10-01 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 515 of the ERCC4 protein (p.Arg515His). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs766111215, ExAC 0.02%). This variant has not been reported in the literature in individuals affected with ERCC4-related conditions. ClinVar contains an entry for this variant (Variation ID: 1048866). 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 histidine 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.
Ambry Genetics RCV002548497 SCV003646324 uncertain significance Inborn genetic diseases 2022-10-06 criteria provided, single submitter clinical testing The c.1544G>A (p.R515H) alteration is located in exon 8 (coding exon 8) of the ERCC4 gene. This alteration results from a G to A substitution at nucleotide position 1544, causing the arginine (R) at amino acid position 515 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001354216 SCV001548773 uncertain significance not provided no assertion criteria provided clinical testing The ERCC4 p.R515H variant was not identified in the literature nor was it identified in COSMIC or ClinVar. The variant was identified in dbSNP (ID: rs766111215) and in control databases in 3 of 251160 chromosomes at a frequency of 0.00001194 (Genome Aggregation Database March 6, 2019, v2.1.1). The p.R515 residue is not conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) do not suggest a high likelihood of impact to the protein; 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 (Splice AI exome) do not predict a deleterious effect on splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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