VCV000403731.7 - ClinVar

NM_003937.3(KYNU):c.1045_1051del (p.Phe349fs)

Germline

Classification

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.

(5)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_003937.3(KYNU):c.1045_1051del (p.Phe349fs)

Variation ID: 403731 Accession: VCV000403731.7

Type and length

Deletion, 7 bp

Location

Cytogenetic: 2q22.2 2: 143040430-143040436 (GRCh38) [ NCBI UCSC ] 2: 143797999-143798005 (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	Aug 5, 2017	May 7, 2024	Nov 7, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_003937.3:c.1045_1051del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_003928.1:p.Phe349fs	frameshift
NM_003937.3:c.1045_1051delTTTAAGC MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		frameshift
NM_001199241.2:c.1045_1051del	NP_001186170.1:p.Phe349fs	frameshift
NM_003937.2:c.1045_1051delTTTAAGC
NC_000002.12:g.143040431_143040437del
NC_000002.11:g.143798000_143798006del
NG_023254.1:g.167806_167812del
NG_023254.2:g.167769_167775del

... more HGVS ... less HGVS

Protein change

F349fs

Other names

KYNU, 7-BP DEL, NT1045

Canonical SPDI

NC_000002.12:143040429:CTTTAAGC:C

Functional consequence Help The 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]

Global minor allele frequency (GMAF) Help The 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

ClinGen: CA1896990 OMIM: 605197.0005 dbSNP: rs770642379 VarSome

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
Gene	OMIM	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.
KYNU		-	-	GRCh38 GRCh37	81	105

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.
Congenital NAD deficiency disorder	Pathogenic (1)	criteria provided, single submitter	Dec 23, 2016	RCV000496114.2
not provided	Pathogenic (1)	criteria provided, single submitter	Nov 7, 2023	RCV000520521.3
Vertebral, cardiac, renal, and limb defects syndrome 2	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Sep 29, 2023	RCV000505812.4

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 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 (Dec 23, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Congenital NAD deficiency disorder multiple congenital malformations (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Embryology Laboratory, Victor Chang Cardiac Research Institute Accession: SCV000540923.1 First in ClinVar: Aug 05, 2017 Last updated: Aug 05, 2017	Publications: PubMed (1) PubMed: 28792876 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 novel (ExAC MAF 0). The patient is compound heterzygous for this variant and another protein truncating variant in the same KYNU gene (NM_003937.2:c.468T>A). 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
Pathogenic (Nov 07, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000618083.4 First in ClinVar: Dec 19, 2017 Last updated: Nov 25, 2023	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 damaging effect on enzyme activity (PMID: 28792876); This variant is associated with the following publications: (PMID: 28792876) (less)
Pathogenic (Sep 29, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Vertebral, cardiac, renal, and limb defects syndrome 2 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004183449.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023
Pathogenic (May 05, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Vertebral, cardiac, renal, and limb defects syndrome 2 Affected status: unknown Allele origin: germline	Molecular Genetics, Royal Melbourne Hospital Additional submitter: Shariant Australia, Australian Genomics Accession: SCV004812278.1 First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024	Publications: PubMed (1) PubMed: 28792876 Comment: This sequence change in KYNU is a frameshift variant predicted to cause a premature stop codon, p.(Phe349Lysfs4), in biologically relevant exon 13/14 leading to nonsense-mediated … (more) This sequence change in KYNU is a frameshift variant predicted to cause a premature stop codon, p.(Phe349Lysfs4), in biologically relevant exon 13/14 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PMID: 28792876). The highest population minor allele frequency in the population database gnomAD v2.1 is 0.006% (8/128,530 alleles) in the European (non-Finnish) population, which is consistent with vertebral, cardiac, renal, and limb defects syndrome. This variant has been detected in an individual with vertebral, cardiac, renal, and limb defects syndrome compound heterozygous with a pathogenic variant and was confirmed in trans by parental testing (PMID: 28792876). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PM3, PM2_Supporting. (less)
Pathogenic (Mar 06, 2024)	no assertion criteria provided Method: literature only	VERTEBRAL, CARDIAC, RENAL, AND LIMB DEFECTS SYNDROME 2 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000600002.2 First in ClinVar: Sep 26, 2017 Last updated: May 07, 2024	Publications: PubMed (1) PubMed: 28792876 Comment on evidence: For discussion of the 7-bp deletion (c.1045_1051del) in the KYNU gene, resulting in a frameshift and premature termination (Phe349LysfsTer4), that was found in compound heterozygous … (more) For discussion of the 7-bp deletion (c.1045_1051del) in the KYNU gene, resulting in a frameshift and premature termination (Phe349LysfsTer4), that was found in compound heterozygous state in a patient (SCV000540923) with vertebral, cardiac, renal, and limb defects syndrome-2 (VCRL2; 617661) by Shi et al. (2017), see 605197.0004. (less)

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 protein truncating variant and novel (ExAC MAF 0). The patient is compound heterzygous for this variant and another protein truncating variant in the same KYNU gene (NM_003937.2:c.468T>A). 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.

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 damaging effect on enzyme activity (PMID: 28792876); This variant is associated with the following publications: (PMID: 28792876)

Comment:

This sequence change in KYNU is a frameshift variant predicted to cause a premature stop codon, p.(Phe349Lysfs*4), in biologically relevant exon 13/14 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PMID: 28792876). The highest population minor allele frequency in the population database gnomAD v2.1 is 0.006% (8/128,530 alleles) in the European (non-Finnish) population, which is consistent with vertebral, cardiac, renal, and limb defects syndrome. This variant has been detected in an individual with vertebral, cardiac, renal, and limb defects syndrome compound heterozygous with a pathogenic variant and was confirmed in trans by parental testing (PMID: 28792876). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PM3, PM2_Supporting.

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.
loss_of_function_variant (SO:0002054) effect on catalytic protein function (VariO:0008)	Method not provided HPLC, NAD/NADH-Gloâ„¢ Assay kit (Promega) KYNU enzyme assay CRISPR/CAS9 germline knockout, mouse phenotyping	Result not provided Plasma 3HK was increased and plasma NAD was decreased in the patient compared to unaffected parents and siblings of the family The protein product of this gene variant had lost enzyme activity Kynu knockout mouse embryos showed similar phenotype as observed in the human patient	Embryology Laboratory, Victor Chang Cardiac Research Institute Accession: SCV000540923.1	Publications PubMed (1) Comment: loss of enzyme function

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
NAD Deficiency, Congenital Malformations, and Niacin Supplementation.	Shi H	The New England journal of medicine	2017	PMID: 28792876

Text-mined citations for rs770642379 ...

These 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 Jun 23, 2024

ClinVar Genomic variation as it relates to human health

NM_003937.3(KYNU):c.1045_1051del (p.Phe349fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs770642379 ...