Submissions for variant NM_001170535.3(ATAD3A):c.1582C>T (p.Arg528Trp)

dbSNP: rs1057517686

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000488909	SCV000267601	likely pathogenic	not provided	2016-04-26	criteria provided, single submitter	research	recurrent de novo variant identified in 5 probands
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000412539	SCV000996108	pathogenic	Harel-Yoon syndrome	2018-02-08	criteria provided, single submitter	clinical testing	This variant has been previously reported as a de novo change in multiple unrelated individuals with developmental delay and additional features (PMID: 27640307). An analysis of fibroblasts derived from an affected individual with this variant and the features of Harel-Yoon syndrome showed increased mitochondrial degradation (PMID: 27640307). Similarly, a reduction in mitochondrial content and aberrant mitochondrial morphology were observed in Drosophila harboring this mutation (PMID: 27640307). This variant is absent from the ExAC and gnomAD population databases. Algorithms developed to predict the effect of missense changes on protein function suggest this variant is likely to be deleterious. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the p.Arg576Trp variant in ATAD3A is classified as pathogenic change.
Genomics England Pilot Project, Genomics England	RCV000412539	SCV001759978	pathogenic	Harel-Yoon syndrome		criteria provided, single submitter	clinical testing
GeneDx	RCV000488909	SCV001823919	pathogenic	not provided	2022-02-17	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect including reduction in mitochondria density and number in motor neurons and muscle, as well as an increase in mitophagic vesicles (Harel et al., 2016); Not observed at significant frequency 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: 33146414, 27640307, 28327206, 31019026)
Provincial Medical Genetics Program of British Columbia, University of British Columbia	RCV000412539	SCV002320855	pathogenic	Harel-Yoon syndrome	2022-01-01	criteria provided, single submitter	clinical testing
3billion, Medical Genetics	RCV000412539	SCV002521182	pathogenic	Harel-Yoon syndrome	2022-05-22	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:27640307). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.72; 3Cnet: 0.85). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000225696). The variant has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 27640307). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
OMIM	RCV000412539	SCV000490326	pathogenic	Harel-Yoon syndrome	2020-03-23	no assertion criteria provided	literature only
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000412539	SCV000494159	pathogenic	Harel-Yoon syndrome		flagged submission	research	This variant has been identified as de novo in 5 individuals with delayed motor development and hypotonia. Please see PMID: 27640307 for full description.
University of Washington Center for Mendelian Genomics, University of Washington	RCV000412539	SCV000993446	pathogenic	Harel-Yoon syndrome	2017-05-25	no assertion criteria provided	research