ClinVar Miner

Submissions for variant NM_000400.4(ERCC2):c.139G>A (p.Gly47Arg)

gnomAD frequency: 0.00001  dbSNP: rs1360631927
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Center for Human Genetics Tuebingen RCV001531476 SCV001746588 pathogenic not provided 2021-04-01 criteria provided, single submitter clinical testing
Molecular Genetics, Royal Melbourne Hospital RCV003994304 SCV004812582 pathogenic Xeroderma pigmentosum, group D 2023-03-30 criteria provided, single submitter clinical testing This sequence change in ERCC2 is predicted to replace glycine with arginine at codon 47, p.(Gly47Arg). The glycine residue is highly conserved (100 vertebrates, UCSC), and is a critical residue in the helicase motif located in the helicase ATP-binding domain (PMID: 9238033, 18510924). There is a large physicochemical difference between glycine and arginine. This variant is present in a single individual from the European (non-Finnish) population in the population database gnomAD v3.1 (1/68,026 alleles). This variant has been detected in at least six individuals with xeroderma pigmentosum (XP), XP-Cockayne syndrome complex, Cockayne syndrome or cerebrooculofacioskeletal syndrome. Of those individuals, one individual was homozygous and one was compound heterozygous for the variant and a pathogenic variant that was confirmed in trans (PMID: 15982307, 25716912, 27396511, 27982466, 33369099). The XP-D complementation group was also identified in XP complementation analysis of at least one of these individual's cells, which is highly specific for ERCC2-related XP. In vitro functional assays of the variant demonstrated defective repair activity, and a Drosophila model demonstrated UV hypersensitivity (PMID: 12820975, 25431422, 25716912). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_Strong, PS3_Moderate, PM1, PM2_Supporting, PP3, PP4.
Fulgent Genetics, Fulgent Genetics RCV005023184 SCV005648432 pathogenic Cerebrooculofacioskeletal syndrome 2; Xeroderma pigmentosum, group D; Trichothiodystrophy 1, photosensitive 2024-02-17 criteria provided, single submitter clinical testing

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