ClinVar Miner

Submissions for variant NM_000400.3(ERCC2):c.1847G>C (p.Arg616Pro) (rs376556895)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Fulgent Genetics,Fulgent Genetics RCV000763054 SCV000893535 pathogenic Cerebrooculofacioskeletal syndrome 2; Xeroderma pigmentosum, group D; Trichothiodystrophy 1, photosensitive 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000489442 SCV000577052 pathogenic not provided 2018-12-12 criteria provided, single submitter clinical testing The R616P variant in the ERCC2 gene has been reported previously with another pathogenic variant on the opposite ERCC2 allele (in trans) in multiple individuals with xeroderma pigmentosum and in at least one individual with trichothiodystrophy (Broughton et al., 1994; Takayama et al., 1995; Taylor et al., 1997; Schafer et al., 2013; Lai et al., 2013). The R616P variant is observed in 33/126,360 (0.026%) alleles from individuals of non-Finnish European background in large population cohorts (Lek et al., 2016). The R616P variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In vitro studies on the yeast Rad15 gene, which is homologous to the human ERCC2 gene, showed that the yeast R616P homologous variant is a functional null allele (Taylor et al., 1997). We interpret R616P as a pathogenic variant.
GenomeConnect, ClinGen RCV000509133 SCV000607299 not provided Cerebrooculofacioskeletal syndrome 2; Trichothiodystrophy 1, photosensitive no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Illumina Clinical Services Laboratory,Illumina RCV000312948 SCV000413569 pathogenic Xeroderma pigmentosum, group D 2017-04-27 criteria provided, single submitter clinical testing The ERCC2 c.1847G>C (p.Arg616Pro) variant was identified in a total of 11 compound heterozygotes, including nine exhibiting a xeroderma pigmentosum (XP) phenotype, one with an XP/Cockayne syndrome phenotype, and one with trichothiodystrophy (Taylor et al. 1997; Emmert et al. 2009; Shafer et al. 2013; Lai et al. 2013; Calmels et al. 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.00021 in the European (non-Finnish) population of the Exome Aggregation Consortium. Taylor et al. (1997) demonstrated that the p.Arg616Pro variant was unable to rescue lethality in a yeast complementation assay. When compared to control cell lines exposed to UV, fibroblasts from individuals carrying the p.Arg616Pro variant showed greater levels of apoptosis (Quielle et al. 2001) and reduced nucleotide excision repair capacity (Shafer et al. 2013), and the variant was noted to completely abolish basal transcription (Dubaele et al. 2003). Based on the collective evidence, the p.Arg616Pro variant is classified as pathogenic for xeroderma pigmentosum. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

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