ClinVar Genomic variation as it relates to human health
NM_003937.3(KYNU):c.468T>A (p.Tyr156Ter)
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_003937.3(KYNU):c.468T>A (p.Tyr156Ter)
Variation ID: 403730 Accession: VCV000403730.6
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q22.2 2: 142956235 (GRCh38) [ NCBI UCSC ] 2: 143713804 (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 Aug 5, 2017 Nov 25, 2023 Oct 11, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003937.3:c.468T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003928.1:p.Tyr156Ter nonsense NM_001032998.2:c.468T>A NP_001028170.1:p.Tyr156Ter nonsense NM_001199241.2:c.468T>A NP_001186170.1:p.Tyr156Ter nonsense NC_000002.12:g.142956235T>A NC_000002.11:g.143713804T>A NG_023254.1:g.83610T>A - Protein change
- Y156*
- Other names
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- Canonical SPDI
- NC_000002.12:142956234:T:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- loss_of_function_variant Sequence Ontology [SO:0002054]
- loss of enzyme function [submitted by Embryology Laboratory, Victor Chang Cardiac Research Institute]
- effect on catalytic protein function Variation Ontology [VariO:0008]
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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.
The Genome Aggregation Database (gnomAD) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00005
Trans-Omics for Precision Medicine (TOPMed) 0.00006
The Genome Aggregation Database (gnomAD) 0.00005
The Genome Aggregation Database (gnomAD), exomes 0.00007
Exome Aggregation Consortium (ExAC) 0.00014
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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KYNU | - | - |
GRCh38 GRCh37 |
61 | 85 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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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Pathogenic (1) |
criteria provided, single submitter
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Dec 23, 2016 | RCV000496184.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 11, 2023 | RCV000522905.2 | |
Pathogenic (1) |
no assertion criteria provided
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Oct 30, 2017 | RCV000505808.5 |
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
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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
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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Pathogenic
(Dec 23, 2016)
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criteria provided, single submitter
Method: research
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Congenital NAD deficiency disorder
multiple congenital malformations
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Embryology Laboratory, Victor Chang Cardiac Research Institute
Accession: SCV000540922.1
First in ClinVar: Aug 05, 2017 Last updated: Aug 05, 2017 |
Comment:
This variant was discovered in a North American family. The patient presented multiple congenital malformations affecting vertebrae, heart, kidney among others. This variant is a … (more)
This variant was discovered in a North American family. The patient presented multiple congenital malformations affecting vertebrae, heart, kidney among others. This variant is a protein truncating variant and extremely rare (ExAC MAF 0.0001419). The patient is compound heterzygous for this variant and another protein truncating variant in the same KYNU gene (NM_003937.2:c.1045_1051delTTTAAGC). Her unaffected parents are heterzygous for only one variant. Enzyme assay confirmed that the protein product of this gene variant has lost enzyme activity. Mouse embryos homozygous null for Kynu presented similar phenotype as observed in the patient, and also showed reduced concentration of NAD in the embryonic tissue. (less)
Observation 1:
Number of individuals with the variant: 1
Clinical Features:
Hypoplastic left heart (present) , Short long bone (present) , Frontal bossing (present) , Vertebral segmentation defect (present) , Unilateral renal agenesis (present) , Hypothyroidism … (more)
Hypoplastic left heart (present) , Short long bone (present) , Frontal bossing (present) , Vertebral segmentation defect (present) , Unilateral renal agenesis (present) , Hypothyroidism (present) , Delayed speech and language development (present) (less)
Family history: no
Sex: female
Ethnicity/Population group: North American
Tissue: peripheral blood lymphocytes
Observation 2:
Sex: mixed
Tissue: plasma
Method: HPLC, NAD/NADH-Gloâ„¢ Assay kit (Promega)
Result:
Plasma 3HK was increased and plasma NAD was decreased in the patient compared to unaffected parents and siblings of the family
Observation 3:
Tissue: recombinant enzyme
Method: KYNU enzyme assay
Result:
The protein product of this gene variant had lost enzyme activity
Observation 4:
Sex: mixed
Method: CRISPR/CAS9 germline knockout, mouse phenotyping
Result:
Kynu knockout mouse embryos showed similar phenotype as observed in the human patient
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Pathogenic
(Oct 11, 2023)
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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: SCV000617867.3
First in ClinVar: Dec 19, 2017 Last updated: Nov 25, 2023 |
Comment:
Nonsense 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)
Nonsense 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; This variant is associated with the following publications: (PMID: 28792876, 24463508, 31589614, 34200361) (less)
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Pathogenic
(Oct 30, 2017)
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no assertion criteria provided
Method: literature only
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VERTEBRAL, CARDIAC, RENAL, AND LIMB DEFECTS SYNDROME 2
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000600001.2
First in ClinVar: Sep 26, 2017 Last updated: Nov 02, 2017 |
Comment on evidence:
In a 3-year-old girl, born of unrelated parents of North American origin (family D) with vertebral, cardiac, renal, and limb defects syndrome-2 (VCRL2; 617661), Shi … (more)
In a 3-year-old girl, born of unrelated parents of North American origin (family D) with vertebral, cardiac, renal, and limb defects syndrome-2 (VCRL2; 617661), Shi et al. (2017) identified compound heterozygous truncating mutations in the KYNU gene: a c.468T-A transversion in exon 6, resulting in a tyr156-to-ter (Y156X) substitution, and a 7-bp deletion (c.1045_1051delTTTAAGC; 605197.0005) in exon 13, resulting in a frameshift and premature termination (Phe349LysfsTer4). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variants were filtered against the ExAC database and were classified as pathogenic based on the American College of Medical Genetics guidelines. In vitro functional expression studies showed that the mutations essentially abolished KYNU enzymatic activity. (less)
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Germline Functional Evidence
Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
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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. |
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loss_of_function_variant
effect on catalytic protein function
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Embryology Laboratory, Victor Chang Cardiac Research Institute
Accession: SCV000540922.1
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Comment:
loss of enzyme function
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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NAD Deficiency, Congenital Malformations, and Niacin Supplementation. | Shi H | The New England journal of medicine | 2017 | PMID: 28792876 |
Text-mined citations for rs758865880 ...
HelpRecord last updated Nov 25, 2023
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.