Submissions for variant NM_003491.4(NAA10):c.47A>C (p.His16Pro)

dbSNP: rs2065185202

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Universitätsklinikum Salzburg, Universitätskinderklinik	RCV001195161	SCV001164597	pathogenic	Intellectual disability, severe	2020-02-26	criteria provided, single submitter	clinical testing	We found the variant NAA10 p.(His16Pro) in a girl with severe synodromic ID and skewed X-Inaktivation by exome analysis. The variant is not present in gnomAD and not present in the Munich exome server (~ 19,000 exomes) Our in silico and functional characterization of the NAA10 p.(His16Pro) variant indicate that the major factor contributing to disease in the female patient is loss of NatA-mediated Nt-acetylation and not monomeric NAA10 NAT-, KAT- or non-catalytic activities.
Universitätsklinikum Salzburg, Universitätskinderklinik	RCV001195646	SCV001365394	pathogenic	Intellectual disability	2020-06-01	criteria provided, single submitter	clinical testing	The NAA10 p.(His16Pro) variant was found de novo in a single family in one severely affected girl with skewed X-inaktivation pattern and was absent from large population studies. Additionally, in vitro functional studies indicate that the His16Pro variant impairs NatA complex formation and NatA catalytic activity. In summary, the His16Pro variant meets the criteria to be classified as pathogenic based upon segregation studies, absence from controls, and functional evidence.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001195297	SCV001365615	likely pathogenic	Neurodevelopmental disorder	2019-11-21	criteria provided, single submitter	clinical testing	The p.His16Pro variant in NAA10 has not been previously reported in individuals with neurodevelopmental disorder and was absent from large population studies. The variant was confirmed to be de novo in this an individual with global developmental delay and intellectual disability, hypotonia, delayed visual maturation, muscle spasms, and MRI findings that include thinning of the corpus callosum, cerebral volume loss, and prominent ventricles by the Broad Institute Rare Genomes Project. Computational prediction tools and conservation analysis support that the variant impacts protein function, though this information is not predictive enough to determine pathogenicity on its own. The number of missense variants reported in this region of the NAA10 gene in the general population is lower than expected, suggesting that a missense variant in this region may not be tolerated. In summary, this variant meets criteria to be classified as likely pathogenic for neurodevelopmental disorder with X-linked inheritance based upon de novo occurrence, absence from the general population, and computational predictions. ACMG/AMP Criteria applied: PS2_Moderate, PM2, PP3, PP2.
Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli	RCV002287477	SCV002577694	pathogenic	Microphthalmia, syndromic 1	2022-10-04	criteria provided, single submitter	clinical testing	PS1;PS3;PM1;PM2_supporting