ClinVar Genomic variation as it relates to human health
NM_001161.5(NUDT2):c.186del (p.Ala63fs)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001161.5(NUDT2):c.186del (p.Ala63fs)
Variation ID: 689658 Accession: VCV000689658.25
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 9p13.3 9: 34343181 (GRCh38) [ NCBI UCSC ] 9: 34343179 (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 Sep 20, 2019 May 12, 2024 Mar 28, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001161.5:c.186del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001152.1:p.Ala63fs frameshift NM_001161.5:c.186delA MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
frameshift NM_001244390.1:c.186delA NM_001244390.2:c.186del NP_001231319.1:p.Ala63fs frameshift NM_001244390.2:c.186delA NM_147172.3:c.186del NP_671701.1:p.Ala63fs frameshift NM_147173.3:c.186del NP_671702.1:p.Ala63fs frameshift NC_000009.12:g.34343182del NC_000009.11:g.34343180del - Protein change
- A63fs
- Other names
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- Canonical SPDI
- NC_000009.12:34343180:AA:A
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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
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The frequency of the allele represented by this VCV record.
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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 | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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NUDT2 | - | - |
GRCh38 GRCh37 |
12 | 84 |
Conditions - Germline
Condition
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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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NUDT2-associated condition
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Likely pathogenic (1) |
criteria provided, single submitter
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Jul 30, 2019 | RCV000850407.4 |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 22, 2022 | RCV002225120.4 | |
Pathogenic (1) |
no assertion criteria provided
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- | RCV001533201.3 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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May 3, 2023 | RCV001655608.19 | |
Pathogenic (2) |
criteria provided, single submitter
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Mar 28, 2024 | RCV002251755.4 |
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
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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
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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
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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
(Jul 30, 2019)
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criteria provided, single submitter
Method: clinical testing
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NUDT2-associated condition
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
inherited
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Undiagnosed Diseases Network, NIH
Study: Undiagnosed Diseases Network (NIH), UDN
Accession: SCV000992387.1 First in ClinVar: Sep 20, 2019 Last updated: Sep 20, 2019 |
Number of individuals with the variant: 1
Clinical Features:
Steppage gait (present) , Sensorimotor neuropathy (present) , Retrognathia (present) , Progressive inability to walk (present) , Positive Romberg sign (present) , Poor coordination (present) … (more)
Steppage gait (present) , Sensorimotor neuropathy (present) , Retrognathia (present) , Progressive inability to walk (present) , Positive Romberg sign (present) , Poor coordination (present) , Narrow forehead (present) , Mixed demyelinating and axonal polyneuropathy (present) , Midface retrusion (present) , Intellectual disability (present) , Hypertension (present) , High palate (present) , Hand muscle weakness (present) , Gait imbalance (present) , Gait disturbance (present) , Foot dorsiflexor weakness (present) , Falls (present) , Facial diplegia (present) , Exotropia (present) , Dysdiadochokinesis (present) , Dysarthria (present) , Distal sensory impairment (present) , Distal muscle weakness (present) , Cognitive impairment (present) , Calf muscle hypoplasia (present) , Bilateral ptosis (present) , Astigmatism (present) , Areflexia (present) (less)
Age: 20-29 years
Sex: male
Ethnicity/Population group: Hispanic
Testing laboratory: HudsonAlpha Clinical Services Lab, LLC,HudsonAlpha Clinical Services Lab, LLC
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Pathogenic
(Dec 09, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001871032.3
First in ClinVar: Sep 19, 2021 Last updated: Dec 17, 2022 |
Comment:
Frameshift variant predicted to result in protein truncation as the last 85 amino acids are lost and replaced with 2 incorrect amino acids, although loss-of-function … (more)
Frameshift variant predicted to result in protein truncation as the last 85 amino acids are lost and replaced with 2 incorrect amino acids, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 31607746, 33058507, 27535533) (less)
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Likely pathogenic
(May 03, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV004270546.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has … (more)
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. ClinVar contains an entry for this variant (Variation ID: 689658). This premature translational stop signal has been observed in individuals with NUDT2-related conditions (PMID: 33058507). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs529087882, gnomAD 0.02%). This sequence change creates a premature translational stop signal (p.Ala63Glnfs*3) in the NUDT2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 85 amino acid(s) of the NUDT2 protein. (less)
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Likely pathogenic
(Apr 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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Complex neurodevelopmental disorder
Affected status: unknown
Allele origin:
germline
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Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002503866.2
First in ClinVar: Apr 28, 2022 Last updated: Apr 15, 2024 |
Comment:
This sequence change is a deletion of 1 bp in exon 5 (of 5) of NUDT2 that is predicted to create a premature termination codon … (more)
This sequence change is a deletion of 1 bp in exon 5 (of 5) of NUDT2 that is predicted to create a premature termination codon at position 65, p.(Ala63Glnfs*3). While this is not anticipated to result in nonsense mediated decay, it is expected to remove the last 83 amino acids (greater than half of the protein). Loss of function has recently been established as a mechanism of disease for this gene (PMID: 27431290, 30059600, 33058507). The variant is present in a large population cohort at a frequency of 0.01% (29/251,412 alleles, 0 homozygotes in gnomAD v2.1). The variant has been identified in the homozygous state in two unrelated individuals with intellectual disability and polyneuropathy, and segregates to a similarly affected sibling in one of these families (PMID: 33058507). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PVS1_Strong, PM2, PM3, PP1. (less)
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Likely pathogenic
(Jan 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV002498025.13
First in ClinVar: Apr 08, 2022 Last updated: May 12, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Mar 28, 2024)
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criteria provided, single submitter
Method: clinical testing
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Intellectual developmental disorder with or without peripheral neuropathy
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV005040484.1
First in ClinVar: May 07, 2024 Last updated: May 07, 2024 |
Comment:
Variant summary: NUDT2 c.186delA (p.Ala63GlnfsX3) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: NUDT2 c.186delA (p.Ala63GlnfsX3) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, however current evidence is not sufficient to establish loss-of-function variants in NUDT2 as causative of disease. The variant allele was found at a frequency of 0.00012 in 251412 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in NUDT2 causing Intellectual Developmental Disorder With Or Without Peripheral Neuropathy (0.00012 vs ND), allowing no conclusion about variant significance. c.186delA has been reported in the literature in multiple individuals affected with Intellectual Developmental Disorder With Or Without Peripheral Neuropathy. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 689658). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Intellectual disability
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
inherited
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Génétique des Maladies du Développement, Hospices Civils de Lyon
Accession: SCV001748438.1
First in ClinVar: Jul 10, 2021 Last updated: Jul 10, 2021 |
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Pathogenic
(Apr 27, 2022)
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no assertion criteria provided
Method: literature only
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INTELLECTUAL DEVELOPMENTAL DISORDER WITH PERIPHERAL NEUROPATHY
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV002520390.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
Comment on evidence:
In 3 patients from 2 unrelated families with intellectual developmental disorder with peripheral neuropathy (IDDPN; 619844), Diaz et al. (2020) identified a homozygous 1-bp deletion … (more)
In 3 patients from 2 unrelated families with intellectual developmental disorder with peripheral neuropathy (IDDPN; 619844), Diaz et al. (2020) identified a homozygous 1-bp deletion (c.186delA) in the last exon of the NUDT2 gene, predicted to result in a frameshift and premature termination (Ala63GlnfsTer3). The mutation, which was found by whole-genome or whole-exome sequencing, segregated with the disorder in both families; the unaffected parents were heterozygous for the mutation. One family was of Mexican descent and the other was of Cajun descent; there was no evidence for a founder effect. The variant was present at a low frequency in the gnomAD database (0.02% in non-Finnish Europeans and 0.0086% in Latinos). Diaz et al. (2020) noted that since the mutation occurs in the last exon, it may escape nonsense-mediated mRNA decay and produce a truncated protein that could have a toxic cellular effect in peripheral nerves. Functional studies of the variant and studies of patient cells were not performed. In addition to intellectual disability, the patients had electrophysiologic evidence of a progressive sensorineural peripheral neuropathy. (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Novel NUDT2 variant causes intellectual disability and polyneuropathy. | Diaz F | Annals of clinical and translational neurology | 2020 | PMID: 33058507 |
A founder nonsense variant in NUDT2 causes a recessive neurodevelopmental disorder in Saudi Arab children. | Yavuz H | Clinical genetics | 2018 | PMID: 30059600 |
Clinical genomics expands the morbid genome of intellectual disability and offers a high diagnostic yield. | Anazi S | Molecular psychiatry | 2017 | PMID: 27431290 |
Text-mined citations for rs529087882 ...
HelpRecord last updated May 12, 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.