ClinVar Genomic variation as it relates to human health

Reported previously in the heterozygous state in multiple individuals with ERF-related clinical features referred for genetic testing at GeneDx and in the published literature (Twigg et al., 2013; Glass et al., 2019); Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 148 amino acids are lost and replaced with 9 incorrect amino acids; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30758909, 23354439, 32370745)

Variant summary: ERF c.1201_1202delAA (p.Lys401GlufsX10) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4.2e-06 in 236032 control chromosomes in gnomAD. c.1201_1202delAA has been reported in the literature in multiple individuals and families affected with ERF-Related Disorders (example: Twigg_2013, Korberg_2020, Glass_2019). These data indicate that the variant is very likely to 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: 30758909, 32370745, 23354439). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

This variant has been identified by standard clinical testing. female patient with craniosynostosis and developmental disorder, inherited from affected father Selected ACMG criteria: Pathogenic (I):PP5;PS4;PVS1

For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with craniosynostosis (PMID: 23354439, 30758909, 32370745). ClinVar contains an entry for this variant (Variation ID: 420168). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Lys401Glufs*10) in the ERF gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 148 amino acid(s) of the ERF protein.

This sequence variant is a two nucleotide deletion (delTT) in exon 4 of 4 of the ERF gene and results in an early termition codon 10 amino acids downstream of the frameshift at Lys401. This variant is not predicted to result in nonsense mediated decay. However, early termitions downstream of this position have reported as pathogenic (ClinVar). This is a previously reported variant (ClinVar 420168) that has been observed in multiple individuals affected by craniosynostosis (PMID: 30758909, 32370745). This variant is de novo; however, it is present in the gnomAD population dataset (1 of 236032 alleles 0.0004%). Based upon the evidence, we consider this variant to be pathogenic. ACMG Criteria: PM2, PS2, PS4, PVS1

The ERF c.1201_1202delAA variant is predicted to result in a frameshift and premature protein termination (p.Lys401Glufs*10). This variant has been reported in individuals with syndromic craniosynostosis and in an individual with sagittal synostosis (Twigg et al. 2013. PubMed ID: 23354439; Glass et al. 2019. PubMed ID: 30758909; Körberg et al. 2020. PubMed ID: 32370745). This variant has also been reported in individuals with neurodevelopmental disorders and Noonan syndrome-like features (Table S1, Kaplanis et al. 2020. PubMed ID: 33057194; Dentici et al. 2024. PubMed ID: 38824261; Orsini et al. 2024. PubMed ID: 38674371). This variant has been reported de novo (Kaplanis et al. 2020. PubMed ID: 33057194; Dentici et al. 2024. PubMed ID: 38824261). This variant is reported in 0.00095% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is reported as pathogenic/likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/420168/). Frameshift variants in ERF are expected to be pathogenic. This variant is interpreted as pathogenic.