Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (exon 2 of 10). (P) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 12 heterozygotes, 0 homozygotes). (P) 0703 - Comparable variants have moderate previous evidence for pathogenicity. Other variants predicted to cause NMD have been reported as pathogenic (PMID: 31755961, 32462209). (P) 0802 - Moderate previous evidence of pathogenicity in unrelated individuals. This variant has been previously reported in patients with neurodegenerative disorder exacerbated by febrile illnesses. (ClinVar, PMID: 30576410, 32462209). (P) 1002 - Moderate functional evidence supporting abnormal protein function. Functional studies show that this variant causes impaired localisation of protein (PMID: 32462209). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
ClinVar Genomic variation as it relates to human health
NM_001242882.2(NAXD):c.54_57del (p.Ala20fs)
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.
(7)
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
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001242882.2(NAXD):c.54_57del (p.Ala20fs)
Variation ID: 617759 Accession: VCV000617759.13
- Type and length
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Deletion, 4 bp
- Location
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Cytogenetic: 13q34 13: 110622220-110622223 (GRCh38) [ NCBI UCSC ] 13: 111274567-111274570 (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 Feb 18, 2019 Oct 8, 2024 Sep 17, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001242882.2:c.54_57del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001229811.1:p.Ala20fs frameshift NM_001242881.2:c.108_111del NP_001229810.1:p.Ala38fs frameshift NM_001242882.1:c.54_57delAAGA NM_001242883.2:c.57-5216_57-5213del intron variant NM_018210.3:c.108_111del NM_018210.3:c.108_111delAAGA NM_018210.4:c.108_111del NP_060680.2:p.Ala38fs frameshift NR_040103.1:n.196_199del non-coding transcript variant NR_040104.1:n.196_199del non-coding transcript variant NC_000013.11:g.110622223_110622226del NC_000013.10:g.111274570_111274573del - Protein change
- A20fs, A38fs
- Other names
- -
- Canonical SPDI
- NC_000013.11:110622219:AGAAAGA:AGA
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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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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.
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- 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. |
|||
| NAXD | - | - |
GRCh38 GRCh37 |
142 | 279 | |
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 (4) |
criteria provided, multiple submitters, no conflicts
|
Oct 19, 2020 | RCV000755012.9 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Sep 17, 2023 | RCV001855857.5 | |
|
NAXD-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Feb 13, 2024 | RCV003965558.2 |
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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|---|---|---|---|---|---|
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Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
NAD(P)HX dehydratase deficiency
Affected status: yes
Allele origin:
inherited
|
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Accession: SCV002053753.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
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Pathogenic
(Oct 19, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
NAD(P)HX dehydratase deficiency
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002769388.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease … (more)
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (exon 2 of 10). (P) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 12 heterozygotes, 0 homozygotes). (P) 0703 - Comparable variants have moderate previous evidence for pathogenicity. Other variants predicted to cause NMD have been reported as pathogenic (PMID: 31755961, 32462209). (P) 0802 - Moderate previous evidence of pathogenicity in unrelated individuals. This variant has been previously reported in patients with neurodegenerative disorder exacerbated by febrile illnesses. (ClinVar, PMID: 30576410, 32462209). (P) 1002 - Moderate functional evidence supporting abnormal protein function. Functional studies show that this variant causes impaired localisation of protein (PMID: 32462209). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign (less)
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|
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Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
NAD(P)HX dehydratase deficiency
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004047087.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
The frameshift variant c.108_111del (p.Ala38PhefsTer9) has been reported previously in homozygous state in patients affected with NAXD deficiency (Van Bergen NJ. et al., 2019). This … (more)
The frameshift variant c.108_111del (p.Ala38PhefsTer9) has been reported previously in homozygous state in patients affected with NAXD deficiency (Van Bergen NJ. et al., 2019). This variant is reported with the allele frequency (0.004%) in the gnomAD and novel in 1000 genome database. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Abnormality of the nervous system (present) , Developmental regression (present) , Cerebellar ataxia (present) , Hypotonia (present)
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Pathogenic
(Jul 07, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002123001.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This variant is present in population databases (rs773887880, gnomAD 0.01%). For these reasons, this variant has been classified as Pathogenic. Studies have shown that this … (more)
This variant is present in population databases (rs773887880, gnomAD 0.01%). For these reasons, this variant has been classified as Pathogenic. Studies have shown that this premature translational stop signal alters NAXD gene expression (PMID: 32462209). ClinVar contains an entry for this variant (Variation ID: 617759). This variant is also known as c.51_54delAGAA (p.Ala20Phefs*9). This premature translational stop signal has been observed in individuals with clinical features of progressive encephalopathy with brain edema and leukoencephalopathy (PMID: 30576410, 32462209). This sequence change creates a premature translational stop signal (p.Ala38Phefs*9) in the NAXD gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NAXD are known to be pathogenic (PMID: 30576410, 32462209). (less)
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Pathogenic
(Sep 17, 2023)
|
criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV005080461.1
First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024 |
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more)
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Published functional studies demonstrate a loss of protein expression (Borna et al., 2020); This variant is associated with the following publications: (PMID: 32462209, 30576410) (less)
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: literature only
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ENCEPHALOPATHY, PROGRESSIVE, EARLY-ONSET, WITH BRAIN EDEMA AND/OR LEUKOENCEPHALOPATHY, 2
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000882836.2
First in ClinVar: Feb 18, 2019 Last updated: Sep 19, 2020 |
Comment on evidence:
In a 1-year-old girl (patient 3) with early-onset progressive encephalopathy with brain edema and/or leukoencephalopathy-2 (PEBEL2; 618321), Van Bergen et al. (2019) identified a homozygous … (more)
In a 1-year-old girl (patient 3) with early-onset progressive encephalopathy with brain edema and/or leukoencephalopathy-2 (PEBEL2; 618321), Van Bergen et al. (2019) identified a homozygous 4-bp deletion (c.51_54delAGAA, NM_01242882.1) in exon 2 of in the NAXD gene, predicted to result in a frameshift and premature termination (Ala20PhefsTer9). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was found in heterozygous state at a low frequency in the gnomAD database (4.47 x 10(-5)). In a 7-year-old boy with PEBEL2, Borna et al. (2020) identified compound heterozygous mutations in the NAXD gene: c.51_54delAGAA and a 1-bp deletion (c.44delG; 615910.0006) predicted to result in a frameshift and premature termination (Arg15GlnfsTer3). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Both mutations are located in the mitochondria-targeted isoform of NAXD. The c.44delG mutation was not found in the dbSNP, gnomAD, or 3.5KJPN database. Overexpression of the either mutation in HEK293FT cells showed loss of protein expression. (less)
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Pathogenic
(Feb 13, 2024)
|
no assertion criteria provided
Method: clinical testing
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NAXD-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004780230.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
The NAXD c.108_111delAAGA variant is predicted to result in a frameshift and premature protein termination (p.Ala38Phefs*9). This variant has been associated with NAD(P)HX dehydratase (NAXD) … (more)
The NAXD c.108_111delAAGA variant is predicted to result in a frameshift and premature protein termination (p.Ala38Phefs*9). This variant has been associated with NAD(P)HX dehydratase (NAXD) deficiency (reported as c.54_57delAAGA using another transcript in Van Bergen et al. 2019. PubMed ID: 30576410). This variant is reported in 0.0086% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in NAXD are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
|
Comment:
Comment:
The frameshift variant c.108_111del (p.Ala38PhefsTer9) has been reported previously in homozygous state in patients affected with NAXD deficiency (Van Bergen NJ. et al., 2019). This variant is reported with the allele frequency (0.004%) in the gnomAD and novel in 1000 genome database. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
This variant is present in population databases (rs773887880, gnomAD 0.01%). For these reasons, this variant has been classified as Pathogenic. Studies have shown that this premature translational stop signal alters NAXD gene expression (PMID: 32462209). ClinVar contains an entry for this variant (Variation ID: 617759). This variant is also known as c.51_54delAGAA (p.Ala20Phefs*9). This premature translational stop signal has been observed in individuals with clinical features of progressive encephalopathy with brain edema and leukoencephalopathy (PMID: 30576410, 32462209). This sequence change creates a premature translational stop signal (p.Ala38Phefs*9) in the NAXD gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NAXD are known to be pathogenic (PMID: 30576410, 32462209).
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Published functional studies demonstrate a loss of protein expression (Borna et al., 2020); This variant is associated with the following publications: (PMID: 32462209, 30576410)
Comment:
The NAXD c.108_111delAAGA variant is predicted to result in a frameshift and premature protein termination (p.Ala38Phefs*9). This variant has been associated with NAD(P)HX dehydratase (NAXD) deficiency (reported as c.54_57delAAGA using another transcript in Van Bergen et al. 2019. PubMed ID: 30576410). This variant is reported in 0.0086% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in NAXD are expected to be pathogenic. This variant is interpreted as pathogenic.
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:
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (exon 2 of 10). (P) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 12 heterozygotes, 0 homozygotes). (P) 0703 - Comparable variants have moderate previous evidence for pathogenicity. Other variants predicted to cause NMD have been reported as pathogenic (PMID: 31755961, 32462209). (P) 0802 - Moderate previous evidence of pathogenicity in unrelated individuals. This variant has been previously reported in patients with neurodegenerative disorder exacerbated by febrile illnesses. (ClinVar, PMID: 30576410, 32462209). (P) 1002 - Moderate functional evidence supporting abnormal protein function. Functional studies show that this variant causes impaired localisation of protein (PMID: 32462209). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Comment:
The frameshift variant c.108_111del (p.Ala38PhefsTer9) has been reported previously in homozygous state in patients affected with NAXD deficiency (Van Bergen NJ. et al., 2019). This variant is reported with the allele frequency (0.004%) in the gnomAD and novel in 1000 genome database. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
This variant is present in population databases (rs773887880, gnomAD 0.01%). For these reasons, this variant has been classified as Pathogenic. Studies have shown that this premature translational stop signal alters NAXD gene expression (PMID: 32462209). ClinVar contains an entry for this variant (Variation ID: 617759). This variant is also known as c.51_54delAGAA (p.Ala20Phefs*9). This premature translational stop signal has been observed in individuals with clinical features of progressive encephalopathy with brain edema and leukoencephalopathy (PMID: 30576410, 32462209). This sequence change creates a premature translational stop signal (p.Ala38Phefs*9) in the NAXD gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NAXD are known to be pathogenic (PMID: 30576410, 32462209).
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Published functional studies demonstrate a loss of protein expression (Borna et al., 2020); This variant is associated with the following publications: (PMID: 32462209, 30576410)
Comment:
The NAXD c.108_111delAAGA variant is predicted to result in a frameshift and premature protein termination (p.Ala38Phefs*9). This variant has been associated with NAD(P)HX dehydratase (NAXD) deficiency (reported as c.54_57delAAGA using another transcript in Van Bergen et al. 2019. PubMed ID: 30576410). This variant is reported in 0.0086% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in NAXD are expected to be pathogenic. This variant is interpreted as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| NAD(P)HX dehydratase protein-truncating mutations are associated with neurodevelopmental disorder exacerbated by acute illness. | Borna NN | Brain : a journal of neurology | 2020 | PMID: 32462209 |
| NAD(P)HX dehydratase (NAXD) deficiency: a novel neurodegenerative disorder exacerbated by febrile illnesses. | Zhou J | Brain : a journal of neurology | 2020 | PMID: 31755961 |
| NAD(P)HX dehydratase (NAXD) deficiency: a novel neurodegenerative disorder exacerbated by febrile illnesses. | Van Bergen NJ | Brain : a journal of neurology | 2019 | PMID: 30576410 |
Text-mined citations for rs773887880 ...
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 Oct 13, 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.