Submissions for variant NM_006494.4(ERF):c.1201_1202del (p.Lys401fs)

dbSNP: rs1064794325

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000485362	SCV000568838	pathogenic	not provided	2022-02-10	criteria provided, single submitter	clinical testing	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)
Department of Medical Genetics, Oslo University Hospital	RCV001263207	SCV001437568	pathogenic	Craniosynostosis 4	2017-06-21	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000485362	SCV001447007	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	RCV001374966	SCV001572254	likely pathogenic	Neurodevelopmental disorder	2020-12-22	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000485362	SCV002063781	pathogenic	not provided	2021-12-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001865446	SCV002217517	pathogenic	TWIST1-related craniosynostosis	2021-03-26	criteria provided, single submitter	clinical testing	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.
Department of Endocrinology and Genetics, Fuzhou Children’s Hospital of Fujian Medical University	RCV003313081	SCV004012895	pathogenic	Chitayat syndrome	2023-07-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317236	SCV004021048	pathogenic	ERF-related disorder	2023-06-23	criteria provided, single submitter	clinical testing	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.
Tartaglia Lab, Genetics and Rare Diseases Research Division, Bambino Gesu' Children's Hospital	RCV004586731	SCV004229155	pathogenic	Noonan Syndrome-like developmental disorder	2023-12-31	criteria provided, single submitter	research
Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	RCV001263207	SCV004231696	pathogenic	Craniosynostosis 4	2024-01-12	criteria provided, single submitter	clinical testing	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
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	RCV001263207	SCV005397446	pathogenic	Craniosynostosis 4	2023-07-21	criteria provided, single submitter	clinical testing	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
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001263207	SCV005398264	pathogenic	Craniosynostosis 4	2024-10-09	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with craniosynostosis 4 (MIM#600775). A single recurring missense variant has been reported to cause Chitayat syndrome (MIM#617180), where the mechanism is unclear (PMID: 27738187). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance in some families with craniosynostosis (PMID: 30758909). (I) 0115 - Variants in this gene are known to have variable expressivity, with intrafamilial variability reported for craniosynostosis (PMID: 35852485). (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0701 - Other truncation variants comparable to the one identified in this case have very strong previous evidence for pathogenicity in individuals with craniosynostosis (ClinVar, PMID: 30758909, 23354439, 28808027). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic and pathogenic by multiple clinical laboratories in ClinVar. This variant has also been observed in two unrelated individuals with craniosynostosis, and was confirmed to be paternally inherited in one individual (PMID: 30758909). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000485362	SCV001951889	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000485362	SCV001975199	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003317236	SCV005361999	pathogenic	ERF-related disorder	2024-08-26	no assertion criteria provided	clinical testing	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.