Submissions for variant NM_001037333.3(CYFIP2):c.259C>T (p.Arg87Cys)

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Total submissions: 11

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000656389	SCV000583965	pathogenic	Developmental and epileptic encephalopathy, 65	2019-07-03	criteria provided, single submitter	research
SIB Swiss Institute of Bioinformatics	RCV000656389	SCV000883216	likely pathogenic	Developmental and epileptic encephalopathy, 65	2018-10-15	criteria provided, single submitter	curation	This variant is interpreted as Likely Pathogenic, for Epileptic encephalopathy, early infantile, 65, autosomal dominant. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS2 => De novo (paternity and maternity confirmed) (https://www.ncbi.nlm.nih.gov/pubmed/29534297). PM1 => Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation (https://www.ncbi.nlm.nih.gov/pubmed/29534297).
Mendelics	RCV000656389	SCV001137017	pathogenic	Developmental and epileptic encephalopathy, 65	2019-05-28	criteria provided, single submitter	clinical testing
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000656389	SCV001150082	pathogenic	Developmental and epileptic encephalopathy, 65	2019-07-22	criteria provided, single submitter	clinical testing
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV001174530	SCV001250719	pathogenic	Seizure	2020-04-24	criteria provided, single submitter	clinical testing	Absent from public databases. Considered pathogenic by prediction scores. de novo
Institute of Human Genetics, University of Leipzig Medical Center	RCV000656389	SCV001429290	pathogenic	Developmental and epileptic encephalopathy, 65	2019-05-13	criteria provided, single submitter	clinical testing	This variant was identified as de novo (maternity and paternity confirmed).
Ambry Genetics	RCV001266302	SCV001444475	pathogenic	Inborn genetic diseases	2018-05-15	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001856988	SCV002229087	pathogenic	not provided	2024-02-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 87 of the CYFIP2 protein (p.Arg87Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with CYFIP2-related conditions (PMID: 29534297, 29667327, 30664714). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 430807). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this missense change affects CYFIP2 function (PMID: 29534297). For these reasons, this variant has been classified as Pathogenic.
3billion	RCV000656389	SCV004013648	pathogenic	Developmental and epileptic encephalopathy, 65		criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 29534297). In silico tool predictions suggest damaging effect of the variant on gene or gene product (3Cnet: 0.94). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000430807 / PMID: 29534297). The variant has been previously reported as de novo in a similarly affected individual (PMID: 29534297). Different missense changes at the same codon (p.Arg87His, p.Arg87Leu, p.Arg87Pro, p.Arg87Ser) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000545427, VCV000545429, VCV000802171 / PMID: 29534297, 33149277). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000656389	SCV005399857	pathogenic	Developmental and epileptic encephalopathy, 65	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 developmental and epileptic encephalopathy 65 (MIM#618008). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 33149277). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (PMID: 2953497). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is one of the most commonly reported pathogenic variants in CYFIP2 associated with epileptic encephalopathy; individuals with variants occurring at the p.(Arg87) residue have been consistently reported with a more severe phenotype compared to other pathogenic variants in this gene (ClinVar, PMIDs: 2953497, 33149277). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000656389	SCV000778395	pathogenic	Developmental and epileptic encephalopathy, 65	2020-11-17	no assertion criteria provided	literature only

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