Submissions for variant NM_006494.4(ERF):c.266A>G (p.Tyr89Cys)

dbSNP: rs886041001

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000481720	SCV000570938	pathogenic	not provided	2022-07-06	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30569521, 27738187, 30728880, 30758909, 32592542, 34426522, 31785789)
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000481720	SCV001447676	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
3billion, Medical Genetics	RCV000258152	SCV002318522	pathogenic	Chitayat syndrome	2022-03-22	criteria provided, single submitter	clinical testing	Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000267443). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 30569521, 27738187). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.764>=0.6, 3CNET: 0.97>=0.75). It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Ambry Genetics	RCV002518789	SCV003564122	pathogenic	Inborn genetic diseases	2021-12-17	criteria provided, single submitter	clinical testing	The c.266A>G (p.Y89C) alteration is located in exon 3 (coding exon 3) of the ERF gene. This alteration results from a A to G substitution at nucleotide position 266, causing the tyrosine (Y) at amino acid position 89 to be replaced by a cysteine (C). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration is a recurrent alteration reported in multiple unrelated individuals with Chitayat syndrome. This alteration occurred de novo in at least three separate patients and was inherited from an affected parent in two families (Balasubramanian, 2016; Caro-Contreras, 2019; Shin, 2019; Suter, 2020; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.
Molecular Genetics Lab, CHRU Brest	RCV000258152	SCV004697643	pathogenic	Chitayat syndrome		criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000258152	SCV005049277	pathogenic	Chitayat syndrome	2024-03-06	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000258152	SCV005398927	pathogenic	Chitayat syndrome	2024-10-10	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.5, 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) 0200 - Variant is predicted to result in a missense amino acid change from tyrosine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (v2, v3 and v4). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated Ets domain (DECIPHER]. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar and has been observed as de novo or inherited from an affected parent in the literature in individuals with Chitayat syndrome (PMID: 27738187). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000258152	SCV000328354	pathogenic	Chitayat syndrome	2017-02-21	no assertion criteria provided	literature only