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

dbSNP: rs1064794325

Total submissions: 11

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
Invitae	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 Disorders	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.
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
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