Submissions for variant NM_003491.4(NAA10):c.347G>A (p.Arg116Gln)

dbSNP: rs2065169655

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001786904	SCV002028893	likely pathogenic	not provided	2021-06-16	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27535533)
Invitae	RCV001786904	SCV002211034	uncertain significance	not provided	2021-06-09	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Arg116 amino acid residue in NAA10. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25099252, 29957440). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with NAA10-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glutamine at codon 116 of the NAA10 protein (p.Arg116Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine.
Institute of Human Genetics, University of Goettingen	RCV002246158	SCV002515882	likely pathogenic	Ogden syndrome	2022-05-20	criteria provided, single submitter	clinical testing	For the following reasons, we consider the NAA10 mutation found to be probably pathogenic: a comparison with the gnomAD browser did not provide any evidence that this sequence change is a norm variant that can also be detected in non-affected individuals. The mutation is not currently listed in ClinVar or the HGMD database; A pathogenic mutation (c.346C>T; p.(Arg116Trp)) has already been described at the above amino acid position in affected individuals with intellectual impairment; HGMD: CM129317; Baker SW et al. (2019) J Mol Diagn. 21(1): 38-48). Functional analysis showed that the NAA10 mutant was associated with significantly reduced catalytic activity compared with wild type (Popp B et al. (2015) Eur J Hum Genet. ;23(5): 602-609); the mutation is independently classified as deleterious by four prediction programs; the following ACMG criteria were used for classification: PM2, PM5, PP2, PP3.
PreventionGenetics, part of Exact Sciences	RCV004536315	SCV004109734	uncertain significance	NAA10-related disorder	2023-05-15	criteria provided, single submitter	clinical testing	The NAA10 c.347G>A variant is predicted to result in the amino acid substitution p.Arg116Gln. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Of note, other variants impacting the same amino acid (p.Arg116Trp and p.Arg116Pro) have been reported as de novo in patients with NAA10-related disorders (Rauch et al. 2012. PubMed ID: 23020937; Table S1 in Baker et al. 2019. PubMed ID: 30577886; Supplementary Table 2 in Martin et al. 2021. PubMed ID: 33504798). Although we suspect that the c.347G>A (p.Arg116Gln) variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.