Submissions for variant NM_001658.4(ARF1):c.296G>A (p.Arg99His)

dbSNP: rs1558087712

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Groupe Hospitalier Pitie Salpetriere, UF Genomique du Developpement, Assistance Publique Hopitaux de Paris	RCV000721171	SCV002104220	pathogenic	Periventricular nodular heterotopia 8	2022-03-12	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000721171	SCV003808382	likely pathogenic	Periventricular nodular heterotopia 8	2021-12-10	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000721171	SCV005086683	pathogenic	Periventricular nodular heterotopia 8	2023-12-21	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: 0105 - The mechanism of disease for this gene is not clearly established. However, both gain of function and loss of function for missense variants have been described (PMIDs: 36345169, 37185208). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. p.(Arg99Cys) has been reported in one individual with speech delay (PMID: 37185208). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as a recurring, de novo variant in individuals with brain malformation with delayed myelination, neurodevelopmental abnormalities and/or speech delay with microcephaly and seizures (ClinVar, PMIDs: 36345169, 28868155, 37185208). (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
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000721171	SCV005374493	likely pathogenic	Periventricular nodular heterotopia 8	2024-09-22	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000721171	SCV005874047	pathogenic	Periventricular nodular heterotopia 8	2024-10-09	criteria provided, single submitter	clinical testing	PS3, PS4, PM2, PM6_Strong, PP2, PP3
OMIM	RCV000721171	SCV000852086	pathogenic	Periventricular nodular heterotopia 8	2018-11-13	no assertion criteria provided	literature only
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001579777	SCV001808479	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001579777	SCV001959177	uncertain significance	not provided		no assertion criteria provided	clinical testing