Submissions for variant NM_012199.5(AGO1):c.536TCT[1] (p.Phe180del)

dbSNP: rs1553154062

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000624497	SCV000742221	likely pathogenic	Inborn genetic diseases	2023-04-19	criteria provided, single submitter	clinical testing	The c.539_541delTCT (p.F180del) alteration, located in coding exon 5 of the AGO1 gene, results from an in-frame TCT deletion at nucleotide positions c.539 to c.541. This results in the deletion of a phenylalanine residue at codon 180. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. The p.F180 amino acid is located in the L1 linker domain, which connects the N-terminal and PAZ domains (Yuan, 2005). The L1 linker domain has been shown to interact with the DNA heteroduplex, guide RNA strands, and complementary DNA target strands (Miyoshi, 2016). Interactions between the L1 linker and the DNA target strand play an important role in DNA silencing activity (Miyoshi, 2016). This alteration is predicted to be deleterious by in silico analysis (Choi, 2012). Based on the available evidence, this alteration is classified as likely pathogenic.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System	RCV000678336	SCV000804400	uncertain significance	not provided	2017-08-03	criteria provided, single submitter	provider interpretation	This 10 year old male has a history of autism spectrum disorder, epilepsy, growth hormone deficiency, hypothyroidism, and ADHD combined type. Patient has had multiple EEGs that reportedly showed centrotemporal spikes that were considered epileptiform, though no seizures have been noted. He has reportedly had two normal MRIs. He is heterozygous for a de novo variant (c.539_541delTCT) in AGO1, which causes an in-frame deletion of one amino acid, phenylalanine 180. This variant is absent from gnomAD. This is a gene of uncertain significance; no known human disorders have been clearly associated with this gene. He is also heterozygous for a nonsense POLG variant that was paternally inherited. His father is reportedly unaffected.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000678336	SCV001468031	uncertain significance	not provided	2020-08-17	criteria provided, single submitter	clinical testing
Laboratoire de Génétique Moléculaire, CHU Bordeaux	RCV000678336	SCV001468974	likely pathogenic	not provided		criteria provided, single submitter	clinical testing
Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli	RCV001420239	SCV001622659	likely pathogenic	See cases	2021-04-26	criteria provided, single submitter	clinical testing	PM2_supporting;PM4_moderate;PM6_moderate;PP3_supporting
GeneDx	RCV000678336	SCV001874874	pathogenic	not provided	2025-03-19	criteria provided, single submitter	clinical testing	In-frame deletion of one amino acid in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 35060114, 34930816, 36563181, 35982159, 36980980, 35982160, 33057194, 38412125)
Institute of Human Genetics, University of Leipzig Medical Center	RCV002286416	SCV002576456	pathogenic	Seizure; Self-injurious behavior; Tremor; Intellectual disability, severe; Severe global developmental delay	2022-09-07	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PS2, PS4_MOD, PM1, PM2_SUP, PM4_SUP
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV003155252	SCV005086583	pathogenic	Neurodevelopmental disorder with language delay and behavioral abnormalities, with or without seizures	2024-09-20	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. This gene is associated with neurodevelopmental disorder with language delay and behavioural abnormalities, with or without seizures (MIM#620292). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0213 - In-frame deletion in a non-repetitive region that has high conservation. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0600 - Variant is located in the annotated argonaute linker 1 domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic or likely pathogenic by multiple clinical laboratories in ClinVar. ClinVar also contains some older entries with VUS classifications. This variant has also been reported in six unrelated de novo individuals with neurodevelopmental disorder with intellectual disability, with four individuals also having seizures (PMID: 35060114, 34930816, 36563181). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 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
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV003155252	SCV005441764	pathogenic	Neurodevelopmental disorder with language delay and behavioral abnormalities, with or without seizures	2025-01-02	criteria provided, single submitter	clinical testing
Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine	RCV001264693	SCV001442940	likely pathogenic	Neurodevelopmental abnormality	2020-05-15	no assertion criteria provided	clinical testing
OMIM	RCV003155252	SCV003844058	pathogenic	Neurodevelopmental disorder with language delay and behavioral abnormalities, with or without seizures	2023-03-22	no assertion criteria provided	literature only