Submissions for variant NM_000400.4(ERCC2):c.1847G>A (p.Arg616Gln)

dbSNP: rs376556895

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV001292729	SCV001481358	uncertain significance	Trichothiodystrophy 1, photosensitive	2020-07-28	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Sema4, Sema4	RCV002256728	SCV002531576	likely pathogenic	Xeroderma pigmentosum	2021-05-21	criteria provided, single submitter	curation
Invitae	RCV001780237	SCV003443259	uncertain significance	not provided	2022-09-09	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 616 of the ERCC2 protein (p.Arg616Gln). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of xeroderma pigmentosum (PMID: 22826098, 23800062). This variant is also known as c.1878G>A. ClinVar contains an entry for this variant (Variation ID: 997520). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ERCC2 protein function. This variant disrupts the p.Arg616 amino acid residue in ERCC2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9238033, 11443545, 22234153, 27396511). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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	RCV003469508	SCV004194674	likely pathogenic	Cerebrooculofacioskeletal syndrome 2	2023-05-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002256728	SCV004241445	likely pathogenic	Xeroderma pigmentosum	2023-12-14	criteria provided, single submitter	clinical testing	Variant summary: ERCC2 c.1847G>A (p.Arg616Gln) results in a conservative amino acid change located in the ATP-dependent helicase, C-terminal (IPR006555) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250892 control chromosomes. c.1847G>A has been reported in the literature in trans or at a compound heterozygous state with a second pathogenic missense in at-least two individuals affected with Xeroderma Pigmentosum or mild Sun Sensitivity (examples, Falik-Zaccai_2012, Schafer_2013). Skin cells of whom showed reduced levels of XPD mRNAs, impaired nucleotide excision DNA repair capacity and reduced post-UV cell survival rates. Additionally, at least two variants at the Arg616 residue have been reported as associated with disease (p.Arg616Trp, p.Arg616Pro), suggesting that this codon is functionally important. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22826098, 23800062). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (Likely pathogenic, n=1; VUS, n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003898284	SCV004716686	likely pathogenic	ERCC2-related condition	2023-10-24	criteria provided, single submitter	clinical testing	The ERCC2 c.1847G>A variant is predicted to result in the amino acid substitution p.Arg616Gln. This variant has been reported with other ERCC2 missense variants in an individual with sun sensitivity (Table 1, Falik-Zaccai et al. 2012. PubMed ID: 22826098) and in an individual with xeroderma pigmentosum (Table 1,Schäfer et al. 2013. PubMed ID: 23800062). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-45856059-C-T). Alternate nucleotide changes affecting the same amino acid (p.Arg616Pro and p.Arg616Trp), have been reported in individuals with ERCC2-associated disease (Taylor et al. 1997. PubMed ID: 9238033; Graham et al. 2001. PubMed ID: 11443545). This variant is interpreted as likely pathogenic.