Submissions for variant NM_003491.4(NAA10):c.346C>T (p.Arg116Trp)

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	RCV000128609	SCV000154971	pathogenic	Ogden syndrome	2016-03-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000413890	SCV000491192	pathogenic	not provided	2021-11-28	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect; a reduction in the catalytic activity (Popp et al., 2015); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 25099252, 23871722, 23020937, 27296530, 27094817, 29957440, 30577886)
Institute of Human Genetics, University of Leipzig Medical Center	RCV000128609	SCV001429211	pathogenic	Ogden syndrome	2019-08-08	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000413890	SCV001500676	pathogenic	not provided	2021-01-01	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000128609	SCV003807764	likely pathogenic	Ogden syndrome	2022-10-29	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderated, PM6 moderated
3billion, Medical Genetics	RCV000128609	SCV003841901	pathogenic	Ogden syndrome	2023-02-23	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. In silico tool predictions suggest damaging effect of the variant on gene or gene product (3Cnet: 0.96). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000139644). The variant has been previously reported as de novo in a similarly affected individual (PMID: 27094817). A different missense change at the same codon (p.Arg116Gln) has been reported to be associated with NAA10 related disorder (ClinVar ID: VCV001326724). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV004528848	SCV004046291	pathogenic	NAA10-related disorder		criteria provided, single submitter	clinical testing	This variant has been previously reported as a de novo change in several individuals with NAA10-related disorder (PMID: 25099252, 29957440). In vitro studies using N-terminal acetylation assays demonstrated protein with this variant had significant reduction in the catalytic activity of the enzyme in comparison to wild type protein (PMID: 25099252). The c.346C>T (p.Arg116Trp) variant is absent from the gnomAD population database and thus is presumed to be rare. The c.346C>T (p.Arg116Trp) variant affects a highly conserved amino acid; however, in silico tools used to predict the effect of this variant on protein function yield discordant results. 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 c.346C>T (p.Arg116Trp) variant is classified as a Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004528848	SCV004108891	pathogenic	NAA10-related disorder	2023-10-04	criteria provided, single submitter	clinical testing	The NAA10 c.346C>T variant is predicted to result in the amino acid substitution p.Arg116Trp. This variant has been reported in the heterozygous and hemizygous states in patients with intellectual disability, development delay and eyelid myoclonus; in the majority of cases, this variant was found to be de novo (see for example, Rauch et al. 2012. PubMed ID: 23020937; Valentine et al. 2018. PubMed ID: 29957440; Baker et al. 2019. PubMed ID: 30577886). This variant was also confirmed to be de novo in an individual with intellectual disability and microcephaly tested at PreventionGenetics. This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating it is rare in the general population. This variant is interpreted as pathogenic.
OMIM	RCV000128609	SCV000257346	pathogenic	Ogden syndrome	2015-05-01	no assertion criteria provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000128609	SCV000734762	pathogenic	Ogden syndrome		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000413890	SCV001929008	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000413890	SCV001956497	pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory of Medical Genetics, University of Torino	RCV000128609	SCV002583290	pathogenic	Ogden syndrome	2022-10-09	no assertion criteria provided	research