Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Institute for Genomic Statistics and Bioinformatics, |
RCV001391664 | SCV001593285 | uncertain significance | XFE progeroid syndrome; Fanconi anemia complementation group Q | criteria provided, single submitter | clinical testing | Assessment of c.2087C>T in ERCC4: The heterozygous transversion from C to T at position 14041540 on chromosome 16 was covered with 464 reads and is found with a VAF of 52% in the index patient. The variant is of maternal origin and was covered with a coverage of 155 reads and a VAF of 52% in the mother. The variant leads to the exchange of the amino acid proline, which is highly conserved across very many species, to leucine at position 696 in ERCC4. Bioinformatic prediction programs such as Sift, Poly-Phen, Provean, EIGN, MutationTaster, and UMD Predicor classify the variant c.2087C>T as pathogenic with a CADD score of 33. REVEL and MetaSVM classify this variant as tolerant. According to ACMG guidelines, c.2087C>T is classified as a variant of unclear clinical significance (VUCS). tolerance to sense-altering variations. However, in close proximity, one pathogenic variant (p.Arg689Ser; ClinVar Variation ID: 55824) causal for Fanconi anemia, complementation group Q as well as two other variants of unclear clinical significance (p.Arg701His, ClinVar Variation ID: 858128; p.Arg701Cys, ClinVar Variation ID: 953866) were described as pathogenic. The amino acid substitution p.Pro969 is located in the nuclease domain inside the protein complex, as are p.Arg689Ser or p.Arg701Cys and p.Arg701His. According to ACMG guidelines, c.2087C>T:p is classified as a variant of unclear clinical significance (VUCS). Classification according to ACMG guidelines of c.2087C>T:p.(Pro696Leu) in ERCC4: VUKS - PM2: The variant was identified only rarely (4 heterozygous carriers in 125722 individuals; allele frequency 1.59*10-5) in population genetic studies (GnomAD) and never observed in homozygous status. - PP3: Bioinformatic prediction programs predominantly classify this variant as pathogenic | |
| Baylor Genetics | RCV001788469 | SCV002030244 | uncertain significance | Fanconi anemia complementation group Q | 2021-01-30 | criteria provided, single submitter | clinical testing | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. |
| Institute for Genomic Statistics and Bioinformatics, |
RCV001849516 | SCV002107175 | uncertain significance | Xeroderma pigmentosum, group F | 2022-03-10 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV003771270 | SCV004577272 | uncertain significance | Xeroderma pigmentosum, group F; Cockayne syndrome; Fanconi anemia complementation group Q | 2022-12-24 | criteria provided, single submitter | clinical testing | 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. 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 ERCC4 protein function. ClinVar contains an entry for this variant (Variation ID: 1077179). This variant has not been reported in the literature in individuals affected with ERCC4-related conditions. This variant is present in population databases (rs752894496, gnomAD 0.003%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 696 of the ERCC4 protein (p.Pro696Leu). |