The homozygous c.389T>C , p.(Leu130Pro) NAA80 genetic variant has been reported in 2 Dutch brothers. Parents are heterozygous for this variant. Both individuals show progressive high-frequency sensorineural hearing loss, craniofacial dysmorphisms, developmental delay, and mild proximal and axial muscle weakness. Based on the molecular structure, we predicted and confirmed the NAA80 c.389T>C , p.(Leu130Pro) variant to result in protein destabilization, causing severely decreased NAA80 protein availability. Concurrently, individuals exhibited a ~50% decrease of actin acetylation. NAA80 individual derived fibroblasts and peripheral blood mononuclear cells showed increased migration, increased filopodia counts and increased levels of polymerized actin, in agreement with previous observations in NAA80 knock-out cells. Furthermore, the significant clinical overlap between NAA80 individuals and individuals with pathogenic variants in several actin subtypes reflects the general importance of controlled actin dynamics for the inner ear, brain and muscle.
ClinVar Genomic variation as it relates to human health
NM_001200016.2(NAA80):c.323T>C (p.Leu108Pro)
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.
(2)
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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/Likely pathogenic
2
no assertion criteria provided
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001200016.2(NAA80):c.323T>C (p.Leu108Pro)
Variation ID: 1301869 Accession: VCV001301869.4
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p21.31 3: 50297141 (GRCh38) [ NCBI UCSC ] 3: 50334572 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Oct 30, 2021 Aug 11, 2024 Aug 6, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001200016.2:c.323T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001186945.1:p.Leu108Pro missense NM_003549.4:c.-17-1522T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001200018.2:c.323T>C NP_001186947.1:p.Leu108Pro missense NM_001200029.2:c.-17-1522T>C intron variant NM_001200030.2:c.-17-1522T>C intron variant NM_001200031.2:c.2+2072T>C intron variant NM_001200032.2:c.2+2072T>C intron variant NM_012191.4:c.389T>C NP_036323.2:p.Leu130Pro missense NC_000003.12:g.50297141A>G NC_000003.11:g.50334572A>G - Protein change
- L108P, L130P
- Other names
- -
- Canonical SPDI
- NC_000003.12:50297140:A:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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effect on protein abundance; Variation Ontology [ VariO:0052]
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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.
- -
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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. |
|||
| HYAL3 | - | - |
GRCh38 GRCh37 |
39 | 76 | |
| NAA80 | - | - |
GRCh38 GRCh37 |
- | 37 | |
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. |
|---|---|---|---|---|
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See cases
|
Likely pathogenic (1) |
no assertion criteria provided
|
Oct 21, 2021 | RCV001733812.3 |
| Pathogenic (1) |
no assertion criteria provided
|
Aug 6, 2024 | RCV004577921.2 |
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. |
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Likely pathogenic
(Oct 21, 2021)
|
no assertion criteria provided
Method: clinical testing, in vitro, in vivo
|
See cases
(Autosomal recessive inheritance)
Affected status: not applicable, yes, no
Allele origin:
germline,
not applicable
|
University Medical Center Utrecht, University Utrecht
Accession: SCV001981673.2
First in ClinVar: Oct 30, 2021 Last updated: Nov 20, 2021 |
Comment:
The homozygous c.389T>C , p.(Leu130Pro) NAA80 genetic variant has been reported in 2 Dutch brothers. Parents are heterozygous for this variant. Both individuals show progressive … (more)
The homozygous c.389T>C , p.(Leu130Pro) NAA80 genetic variant has been reported in 2 Dutch brothers. Parents are heterozygous for this variant. Both individuals show progressive high-frequency sensorineural hearing loss, craniofacial dysmorphisms, developmental delay, and mild proximal and axial muscle weakness. Based on the molecular structure, we predicted and confirmed the NAA80 c.389T>C , p.(Leu130Pro) variant to result in protein destabilization, causing severely decreased NAA80 protein availability. Concurrently, individuals exhibited a ~50% decrease of actin acetylation. NAA80 individual derived fibroblasts and peripheral blood mononuclear cells showed increased migration, increased filopodia counts and increased levels of polymerized actin, in agreement with previous observations in NAA80 knock-out cells. Furthermore, the significant clinical overlap between NAA80 individuals and individuals with pathogenic variants in several actin subtypes reflects the general importance of controlled actin dynamics for the inner ear, brain and muscle. (less)
Observation 1:
Clinical Features:
High-frequency sensorineural hearing impairment (present) , Prominence of the zygomatic bone (present) , Congenital ptosis (present) , Progressive sensorineural hearing impairment (present) , Brain imaging … (more)
High-frequency sensorineural hearing impairment (present) , Prominence of the zygomatic bone (present) , Congenital ptosis (present) , Progressive sensorineural hearing impairment (present) , Brain imaging abnormality (present) , Low posterior hairline (present) , Prominent metopic ridge (present) , Tapered finger (present) , Everted lower lip vermilion (present) , Microretrognathia (present) , Synophrys (present) , Downturned corners of mouth (present) , Highly arched eyebrow (present) , Failure to thrive in infancy (present) , Hypertrichosis (present) , Thin upper lip vermilion (present) , Smooth philtrum (present) , Broad nasal tip (present) , Bulbous nose (present) , Feeding difficulties in infancy (present) , Epicanthus (present) , Clinodactyly (present) , Abnormal fear-induced behavior (present) , Motor delay (present) , Long philtrum (present) , Abnormal pinna morphology (present) , Hypertelorism (present) , Low-set ears (present) , Delayed speech and language development (present) , Microcephaly (present) , Anteverted nares (present) , High palate (present) , Hypotonia (present) , Global developmental delay (present) , Intellectual disability (present) , Strabismus (present) , Infantile axial hypotonia (present) , Generalized neonatal hypotonia (present) , Neonatal hypotonia (present) , Generalized hypotonia (present) , Episodic generalized hypotonia (present) , Axial hypotonia (present) , Proximal muscle weakness (present) , Snoring (present) (less)
Age: 10-19 years
Sex: male
Ethnicity/Population group: Mediterrean
Geographic origin: Portugal
Method: Whole Exome Sequencing
Testing laboratory: Wilhelmina Children's Hospital Dept. of Medical Genetics
Date variant was reported to submitter: 2012-10-01
Testing laboratory interpretation: Uncertain significance
Observation 2:
Clinical Features:
Progressive sensorineural hearing impairment (present) , High-frequency hearing impairment (present) , Congenital ptosis (present) , Low posterior hairline (present) , Everted lower lip vermilion (present) … (more)
Progressive sensorineural hearing impairment (present) , High-frequency hearing impairment (present) , Congenital ptosis (present) , Low posterior hairline (present) , Everted lower lip vermilion (present) , Synophrys (present) , Downturned corners of mouth (present) , Highly arched eyebrow (present) , Thin upper lip vermilion (present) , Feeding difficulties in infancy (present) , Epicanthus (present) , Hypertelorism (present) , Low-set ears (present) , Microcephaly (present) , Global developmental delay (present) , Pointed chin (present) , Prominence of the zygomatic bone (present) , Prominent metopic ridge (present) , Microretrognathia (present) , Failure to thrive in infancy (present) , Smooth philtrum (present) , Broad nasal tip (present) , Bulbous nose (present) , Long philtrum (present) , Anteverted nares (present) , Infantile axial hypotonia (present) , Generalized neonatal hypotonia (present) , Neonatal hypotonia (present) , Generalized hypotonia (present) , Episodic generalized hypotonia (present) , Proximal muscle weakness (present) , Axial hypotonia (present) , Sleep apnea (present) , Episodic vomiting (present) (less)
Sex: male
Comment on evidence:
Brother of proband 1.2.
Method: The NAA80 gene was sequenced using specific primers.
Observation 3:
Indication for testing: Segregation
Sex: male
Comment on evidence:
Unaffected brother with heterozygous variant
Observation 4:
Comment on evidence:
Not affected, not carrying one of the NAA80 mutations
Observation 5:
Sex: male
Tissue: Patient derived Fibroblast
Result:
To accurately determine the levels of acetylated actin, the level of N-terminal acetylation of ß- and ?-actin in fibroblasts from NAA80 individuals was analyzed by mass spectrometry. In healthy donors, ~0.5% of beta and gamma-actins were not acetylated. However, for the NAA80 individuals, 25-65% of beta and gamma-actins were not acetylated, depending on the cell type and the type of cytoplasmic actin.
Observation 6:
Sex: male
Tissue: PBMCs
Result:
To accurately determine the levels of acetylated actin, the level of N-terminal acetylation of ß- and ?-actin in PBMCs from NAA80 individuals was analyzed by mass spectrometry. In healthy donors, ~0.5% of beta and gamma-actins were not acetylated. However, for the NAA80 individuals, 25-65% of beta and gamma-actins were not acetylated, depending on the cell type and the type of cytoplasmic actin.
Observation 7:
Sex: male
Tissue: Patient derived Fibroblast
Result:
In NAA80 oatient fibroblasts, NAA80 protein levels were significantly decreased compared to healthy controls .
Observation 8:
Result:
The wild-type and the mutant NAA80 protein with a C-terminal poly-His tag were expressed in Escherichia coli and bacterial extracts were centrifuged and analyzed by SDS-PAGE and western blot. Mutant protein was predominantly insoluble, contrasting with wild-type protein, which was essentially soluble, with only a very small proportion in the sediment. These findings align with the prediction that the NAA80 variant induces defective protein folding.
Observation 9:
Result:
To measure the impact of the NAA80 genetic variant on protein levels in mammalian cells, we infected NAA80 knockout HAP1 cells with constructs expressing mutant or wild type NAA80 cDNA with promoters of different strengths, EF1A being the strongest and SV40 being the weakest promotor. Lower protein levels of mutant NAA80 compared to healthy donors were observed with all promotors
Observation 10:
Result:
Mutant NAA80 was expressed in HAP1 NAA80 knockout cells using different promotors. With the weakest promoter expressing mutant NAA80, we found decreased actin acetylation. Use of a stronger promoter resulted in restoration of actin acetylation, as determined by western blotting with antibodies specific for the acetylated form of beta actin, indicating that the mutated protein still shows residual activity. In addition, we found that expression of low levels of wild-type NAA80 in HAP1 KO cells was already sufficient to reach maximal or near-maximal acetylation. It should be noted that the western blot approach used in this experiment does not allow precise quantification of the level of acetylation.
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Pathogenic
(Aug 06, 2024)
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no assertion criteria provided
Method: literature only
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AURONEURODENTAL SYNDROME (1 family)
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV005049552.2
First in ClinVar: Jun 09, 2024 Last updated: Aug 11, 2024 |
Comment on evidence:
In 2 Portuguese brothers with auroneurodental syndrome (ANDS; 607073), Muffels et al. (2021) identified homozygosity for a c.389T-C transition in the NAA80 gene, resulting in … (more)
In 2 Portuguese brothers with auroneurodental syndrome (ANDS; 607073), Muffels et al. (2021) identified homozygosity for a c.389T-C transition in the NAA80 gene, resulting in a leu130-to-pro (L130P) substitution. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was present in the carrier state in the parents. NAA80 protein expression was reduced in fibroblasts from one of the brothers. Actin acetylation was reduced in fibroblasts and PBMCs from both brothers. (less)
|
Comment:
Germline Functional Evidence
| Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|---|---|---|---|---|
|
effect on protein abundance
|
|
|
University Medical Center Utrecht, University Utrecht
Accession: SCV001981673.2
|
|
Comment:
The homozygous c.389T>C , p.(Leu130Pro) NAA80 genetic variant has been reported in 2 Dutch brothers. Parents are heterozygous for this variant. Both individuals show progressive high-frequency sensorineural hearing loss, craniofacial dysmorphisms, developmental delay, and mild proximal and axial muscle weakness. Based on the molecular structure, we predicted and confirmed the NAA80 c.389T>C , p.(Leu130Pro) variant to result in protein destabilization, causing severely decreased NAA80 protein availability. Concurrently, individuals exhibited a ~50% decrease of actin acetylation. NAA80 individual derived fibroblasts and peripheral blood mononuclear cells showed increased migration, increased filopodia counts and increased levels of polymerized actin, in agreement with previous observations in NAA80 knock-out cells. Furthermore, the significant clinical overlap between NAA80 individuals and individuals with pathogenic variants in several actin subtypes reflects the general importance of controlled actin dynamics for the inner ear, brain and muscle.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay. | Muffels IJJ | Brain communications | 2021 | DOI: 10.1093/braincomms/fcab256 |
| NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay. | Muffels IJJ | Brain communications | 2021 | PMID: 34805998 |
Text-mined citations for rs2109291659 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 25, 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.