This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
ClinVar Genomic variation as it relates to human health
NM_003491.4(NAA10):c.247C>T (p.Arg83Cys)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(19)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic
19
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_003491.4(NAA10):c.247C>T (p.Arg83Cys)
Variation ID: 208664 Accession: VCV000208664.59
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: Xq28 X: 153932410 (GRCh38) [ NCBI UCSC ] X: 153197863 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jun 23, 2016 Oct 20, 2024 Jan 11, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_003491.4:c.247C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003482.1:p.Arg83Cys missense NM_001256119.2:c.247C>T NP_001243048.1:p.Arg83Cys missense NM_001256120.2:c.229C>T NP_001243049.1:p.Arg77Cys missense NC_000023.11:g.153932410G>A NC_000023.10:g.153197863G>A NG_031987.1:g.7745C>T - Protein change
- R83C, R77C
- Other names
- -
- Canonical SPDI
- NC_000023.11:153932409:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| NAA10 | Little evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
155 | 434 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Feb 23, 2023 | RCV000225365.16 | |
| Pathogenic (10) |
criteria provided, multiple submitters, no conflicts
|
Jan 11, 2024 | RCV000255490.53 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 30, 2016 | RCV000190675.13 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Apr 20, 2020 | RCV001257765.9 | |
|
See cases
|
Pathogenic (1) |
criteria provided, single submitter
|
Feb 24, 2022 | RCV002252040.9 |
|
NAA10-related disorder
|
Pathogenic (1) |
criteria provided, single submitter
|
Nov 10, 2023 | RCV003401042.1 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Mar 31, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Ogden syndrome
Affected status: yes
Allele origin:
de novo,
inherited
|
Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg
Accession: SCV000267573.2
First in ClinVar: Jun 23, 2016 Last updated: Jun 23, 2016
Comment:
Variant was found de novo in 6 females. Inherited in one affected female through germline mosaicism in a mother; more severely affected and deceased (age … (more)
Variant was found de novo in 6 females. Inherited in one affected female through germline mosaicism in a mother; more severely affected and deceased (age of one week) brother; maternal germline mosaicism was assumed because exome data did not reveal the mutation in the mother’s blood sample and because of recurrence in a third pregnancy terminated after prenatal diagnosis. (less)
|
Observation 1:
Age: 0-9 years
Sex: female
Observation 2:
Age: 0-9 years
Sex: female
Observation 3:
Age: 0-9 years
Sex: female
Observation 4:
Age: 0-9 years
Sex: female
Observation 5:
Age: 10-19 years
Sex: female
Observation 6:
Age: 0-9 years
Sex: female
Observation 7:
Age: 0-9 years
Sex: female
Observation 8:
Age: 0-9 years
Sex: male
|
|
|
Pathogenic
(Apr 20, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Intellectual disability
(X-linked inheritance)
Affected status: yes
Allele origin:
de novo
|
Diagnostic Laboratory, Strasbourg University Hospital
Accession: SCV001434577.1
First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020 |
Observation 1:
Clinical Features:
Microcephaly (present) , severe intellectual disability (present) , hypotonia (present) , unexplained laughs (present) , normal MRI (present) , delayed walking (18 months old) (present) … (more)
Microcephaly (present) , severe intellectual disability (present) , hypotonia (present) , unexplained laughs (present) , normal MRI (present) , delayed walking (18 months old) (present) , no language (present) (less)
Family history: yes
Age: 0-9 years
Sex: female
Tissue: blood
Method: targeted capture
Observation 2:
Clinical Features:
Severe intellectual disability (present) , hypotonia (present)
Age: 0-9 years
Sex: female
Tissue: blood
Method: targeted capture
|
|
|
Pathogenic
(Oct 23, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
(Unknown mechanism)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001447793.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Global developmental delay (present) , Short stature (present) , Pulmonic stenosis (present) , Blue irides (present) , Ptosis (present) , Hypertelorism (present) , Feeding difficulties … (more)
Global developmental delay (present) , Short stature (present) , Pulmonic stenosis (present) , Blue irides (present) , Ptosis (present) , Hypertelorism (present) , Feeding difficulties (present) (less)
Sex: female
|
|
|
Pathogenic
(Sep 29, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001473397.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
|
|
|
Pathogenic
(Oct 12, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Ogden syndrome
Affected status: yes
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV001520401.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
|
|
|
Pathogenic
(Mar 30, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: yes
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000244115.7
First in ClinVar: Sep 14, 2015 Last updated: Jan 07, 2023 |
Observation 1:
Number of individuals with the variant: 1
Clinical Features:
Global developmental delay (present) , Muscular hypotonia (present) , Prolonged QT interval (present) , Microcephaly (present) , Downslanted palpebral fissures (present) , Thick eyebrow (present) … (more)
Global developmental delay (present) , Muscular hypotonia (present) , Prolonged QT interval (present) , Microcephaly (present) , Downslanted palpebral fissures (present) , Thick eyebrow (present) , Tapered finger (present) , Pes planus (present) , Pectus excavatum (present) , Abnormality of brain morphology (present) (less)
Sex: female
Ethnicity/Population group: Caucasian/Hispanic
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Intellectual disability, severe (present) , Feeding difficulties (present) , Failure to thrive (present) , Gastroesophageal reflux (present) , Laryngomalacia (present) , Recurrent sinusitis (present) , … (more)
Intellectual disability, severe (present) , Feeding difficulties (present) , Failure to thrive (present) , Gastroesophageal reflux (present) , Laryngomalacia (present) , Recurrent sinusitis (present) , Hypertensive disorder (present) , Obstructive sleep apnea syndrome (present) , Astigmatism (present) , Myopia (disease) (present) , Precocious puberty (present) , Gastritis (present) , Gastroparesis (present) , Involuntary movements (present) , Synophrys (present) , Deeply set eye (present) , Short philtrum (present) , Wide mouth (present) , Small hand (present) , Short foot (present) , Intrauterine growth retardation (present) , Muscular hypotonia (present) (less)
Sex: female
Ethnicity/Population group: Caucasian
Observation 3:
Number of individuals with the variant: 1
Clinical Features:
Hypertrophic cardiomyopathy (present) , Atrial septal defect (present) , Ventricular septal defect (present) , Subvalvular aortic stenosis (present) , Global developmental delay (present) , Muscular … (more)
Hypertrophic cardiomyopathy (present) , Atrial septal defect (present) , Ventricular septal defect (present) , Subvalvular aortic stenosis (present) , Global developmental delay (present) , Muscular hypotonia (present) , Microcephaly (present) , Growth delay (present) , Sloping forehead (present) , Wide nose (present) , Low-set ears (present) , Dysphagia (present) , Seizures (present) (less)
Sex: female
Ethnicity/Population group: Hispanic
|
|
|
Pathogenic
(May 12, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000321921.10
First in ClinVar: Oct 09, 2016 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate a damaging effect with an approximately 60% reduction in catalytic activity of NAA10 for all tested oligopeptides in in vitro enzymatic … (more)
Published functional studies demonstrate a damaging effect with an approximately 60% reduction in catalytic activity of NAA10 for all tested oligopeptides in in vitro enzymatic assays (Saunier et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21700266, 25099252, 28628100, 26522270, 32698785, 27094817, 28967461, 30138938, 29100083, 32973342, 34200686, 33504798, 31093388, 31127942, 28135719, 33258288, 31785789) (less)
|
|
|
Pathogenic
(Jan 11, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002018189.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Feb 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001373962.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 83 of the NAA10 protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 83 of the NAA10 protein (p.Arg83Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with N-terminal acetyltransferase deficiency (PMID: 27094817). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 208664). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects NAA10 function (PMID: 27094817). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Jan 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001334452.25
First in ClinVar: Jun 08, 2020 Last updated: Oct 20, 2024 |
Comment:
NAA10: PM6:Strong, PM2, PM5, PS4:Moderate, PP2, PS3:Supporting
Number of individuals with the variant: 2
|
|
|
Pathogenic
(Feb 24, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Ogden syndrome
Affected status: yes
Allele origin:
de novo
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV002102462.1
First in ClinVar: Mar 05, 2022 Last updated: Mar 05, 2022 |
Comment:
_x000D_ Criteria applied: PS2_VSTR, PS4_MOD, PM1, PM2_SUP, PM5_SUP, PP3
|
|
|
Pathogenic
(Feb 24, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
See cases
Affected status: yes
Allele origin:
germline
|
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002523044.1
First in ClinVar: Jun 11, 2022 Last updated: Jun 11, 2022 |
Comment:
ACMG classification criteria: PS3, PS4, PM2, PM6
Clinical Features:
Short stature (present) , Neurodevelopmental abnormality (present) , Abnormality of mental function (present)
|
|
|
Pathogenic
(Feb 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Ogden syndrome
Affected status: yes
Allele origin:
unknown
|
3billion
Accession: SCV003841470.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. The variant has been confirmed to be de … (more)
The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. The variant has been confirmed to be de novo as shown in the table above Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 27094817, 27094817). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.58; 3Cnet: 0.90). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000208664) and a different missense change at the same codon (p.Arg83His / ClinVar ID: VCV000691256) have been previously reported as pathogenic/likely pathogenic with strong evidence. The variant has been previously reported as de novo in a similarly affected individual (PMID: 27094817). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Prolonged neonatal jaundice (present) , Fetal pyelectasis (present) , Global developmental delay (present) , Delayed speech and language development (present) , Delayed fine motor development … (more)
Prolonged neonatal jaundice (present) , Fetal pyelectasis (present) , Global developmental delay (present) , Delayed speech and language development (present) , Delayed fine motor development (present) , Delayed gross motor development (present) , Delayed early-childhood social milestone development (present) , Abnormal facial shape (present) , Coarse facial features (present) , Hypertelorism (present) , Synophrys (present) , Thick eyebrow (present) , Long eyelashes (present) , Depressed nasal bridge (present) , Bulbous nose (present) , Macroglossia (present) , Proptosis (present) , Long philtrum (present) , Thin upper lip vermilion (present) , Low-set ears (present) , Low posterior hairline (present) , Ankle flexion contracture (present) , Failure to thrive (present) (less)
|
|
|
Pathogenic
(Nov 10, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
NAA10-related disorder
Affected status: yes
Allele origin:
de novo
|
Daryl Scott Lab, Baylor College of Medicine
Accession: SCV004102714.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
|
|
|
Pathogenic
(May 26, 2017)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes
Accession: SCV000778261.1
First in ClinVar: Oct 09, 2016 Last updated: Oct 09, 2016 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001741612.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001958503.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001974508.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
|
|
|
Pathogenic
(Sep 08, 2022)
|
no assertion criteria provided
Method: literature only
|
OGDEN SYNDROME
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV001748650.2
First in ClinVar: Jul 10, 2021 Last updated: Sep 17, 2022 |
Comment on evidence:
In 6 unrelated females and a brother-sister pair with Ogden syndrome (OGDNS; 300855), Saunier et al. (2016) identified heterozygosity or hemizygosity for a c.247C-T transition … (more)
In 6 unrelated females and a brother-sister pair with Ogden syndrome (OGDNS; 300855), Saunier et al. (2016) identified heterozygosity or hemizygosity for a c.247C-T transition (c.247C-T, NM_003491.3) in the NAA10 gene, resulting in an arg83-to-cys (R83C) substitution. The mutations, which were found by trio whole-exome sequencing or by sequencing of a panel of genes associated with intellectual disability, were de novo in the 11 unrelated females and were due to maternal germline mosaicism in the sib pair. In vitro assays of mutant NAA10 with the R83C mutation demonstrated reduced catalytic activity and a higher Km compared to wildtype, indicating reduced affinity to acetyl-CoA. In 11 unrelated females with OGDNS, Cheng et al. (2019) identified a de novo heterozygous c.247C-T transition in exon 5 of the NAA10 gene, resulting in an R83C substitution. The mutation was found by exome sequencing; it was not present in the gnomAD database. In vitro functional expression studies indicated that the mutation may have increased activity compared to wildtype in certain circumstances. In an 18-year-old woman with OGDNS, Maini et al. (2021) identified heterozygosity for the R83C mutation in the NAA10 gene. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was shown to be de novo. (less)
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
Published functional studies demonstrate a damaging effect with an approximately 60% reduction in catalytic activity of NAA10 for all tested oligopeptides in in vitro enzymatic assays (Saunier et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21700266, 25099252, 28628100, 26522270, 32698785, 27094817, 28967461, 30138938, 29100083, 32973342, 34200686, 33504798, 31093388, 31127942, 28135719, 33258288, 31785789)
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 83 of the NAA10 protein (p.Arg83Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with N-terminal acetyltransferase deficiency (PMID: 27094817). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 208664). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects NAA10 function (PMID: 27094817). For these reasons, this variant has been classified as Pathogenic.
Comment:
NAA10: PM6:Strong, PM2, PM5, PS4:Moderate, PP2, PS3:Supporting
Comment:
_x000D_ Criteria applied: PS2_VSTR, PS4_MOD, PM1, PM2_SUP, PM5_SUP, PP3
Comment:
ACMG classification criteria: PS3, PS4, PM2, PM6
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. The variant has been confirmed to be de novo as shown in the table above Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 27094817, 27094817). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.58; 3Cnet: 0.90). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000208664) and a different missense change at the same codon (p.Arg83His / ClinVar ID: VCV000691256) have been previously reported as pathogenic/likely pathogenic with strong evidence. The variant has been previously reported as de novo in a similarly affected individual (PMID: 27094817). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Comment:
Published functional studies demonstrate a damaging effect with an approximately 60% reduction in catalytic activity of NAA10 for all tested oligopeptides in in vitro enzymatic assays (Saunier et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21700266, 25099252, 28628100, 26522270, 32698785, 27094817, 28967461, 30138938, 29100083, 32973342, 34200686, 33504798, 31093388, 31127942, 28135719, 33258288, 31785789)
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 83 of the NAA10 protein (p.Arg83Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with N-terminal acetyltransferase deficiency (PMID: 27094817). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 208664). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects NAA10 function (PMID: 27094817). For these reasons, this variant has been classified as Pathogenic.
Comment:
NAA10: PM6:Strong, PM2, PM5, PS4:Moderate, PP2, PS3:Supporting
Comment:
_x000D_ Criteria applied: PS2_VSTR, PS4_MOD, PM1, PM2_SUP, PM5_SUP, PP3
Comment:
ACMG classification criteria: PS3, PS4, PM2, PM6
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. The variant has been confirmed to be de novo as shown in the table above Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 27094817, 27094817). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.58; 3Cnet: 0.90). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000208664) and a different missense change at the same codon (p.Arg83His / ClinVar ID: VCV000691256) have been previously reported as pathogenic/likely pathogenic with strong evidence. The variant has been previously reported as de novo in a similarly affected individual (PMID: 27094817). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Clinical Manifestations in a Girl with NAA10-Related Syndrome and Genotype-Phenotype Correlation in Females. | Maini I | Genes | 2021 | PMID: 34200686 |
| A novel NAA10 p.(R83H) variant with impaired acetyltransferase activity identified in two boys with ID and microcephaly. | Ree R | BMC medical genetics | 2019 | PMID: 31174490 |
| Phenotypic and biochemical analysis of an international cohort of individuals with variants in NAA10 and NAA15. | Cheng H | Human molecular genetics | 2019 | PMID: 31127942 |
| Expanding the Phenotype Associated with NAA10-Related N-Terminal Acetylation Deficiency. | Saunier C | Human mutation | 2016 | PMID: 27094817 |
| http://www.LOVD.nl/NAA10_000006 | - | - | - | - |
Text-mined citations for this variant ...
HelpRecord last updated Nov 10, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.