ClinVar Miner

Submissions for variant NM_000400.4(ERCC2):c.2041G>A (p.Asp681Asn)

gnomAD frequency: 0.00001  dbSNP: rs121913023
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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 RCV003114198 SCV003788371 pathogenic not provided 2024-07-10 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 681 of the ERCC2 protein (p.Asp681Asn). This variant is present in population databases (rs121913023, gnomAD 0.004%). This missense change has been observed in individuals with ERCC2-related conditions (PMID: 11443545, 18470933, 23232694). ClinVar contains an entry for this variant (Variation ID: 16787). 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 with a positive predictive value of 80%. This variant disrupts the p.Asp681 amino acid residue in ERCC2. Other variant(s) that disrupt this residue have been observed in individuals with ERCC2-related conditions (PMID: 22234153, 23800062, 28749383), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000018277 SCV004194612 pathogenic Cerebrooculofacioskeletal syndrome 2 2024-03-08 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003488344 SCV004241045 uncertain significance not specified 2023-12-13 criteria provided, single submitter clinical testing Variant summary: ERCC2 c.2041G>A (p.Asp681Asn) results in a conservative amino acid change located in the ATP-dependent helicase, C-terminal domain (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 2e-05 in 251346 control chromosomes (gnomAD). c.2041G>A has been reported in the literature as a compound heterozygous genotype in at least one individual affected with Xeroderma Pigmentosum (Lehmann_2001, Boyle_2008), an individual with trichothiodystrophy (Zhou_2013), and an individual with UV-sensitive COFS Syndrome (Grham_2001). 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: 18470933, 11443545, 11156600, 23232694). One submitter has cited a clinical-significance assessment for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Ambry Genetics RCV005328199 SCV005994136 likely pathogenic Inborn genetic diseases 2024-12-11 criteria provided, single submitter clinical testing The c.2041G>A (p.D681N) alteration is located in exon 21 (coding exon 21) of the ERCC2 gene. This alteration results from a G to A substitution at nucleotide position 2041, causing the aspartic acid (D) at amino acid position 681 to be replaced by an asparagine (N). Based on data from gnomAD, the A allele has an overall frequency of 0.002% (5/251346) total alleles studied. The highest observed frequency was 0.004% (5/113664) of European (non-Finnish) alleles. This variant has been identified in the homozygous state and/or in conjunction with other ERCC2 variant(s) in individual(s) with features consistent with ERCC2-related spectrum disorders (Graham, 2001; Boyle, 2008; Zhou, 2013; Tamura, 2012). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic.
OMIM RCV000018277 SCV000038556 pathogenic Cerebrooculofacioskeletal syndrome 2 2001-08-01 no assertion criteria provided literature only

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