VCV000403728.1 - ClinVar

NM_012205.3(HAAO):c.558G>A (p.Trp186Ter)

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.

(3)

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_012205.3(HAAO):c.558G>A (p.Trp186Ter)

Variation ID: 403728 Accession: VCV000403728.1

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2p21 2: 42769785 (GRCh38) [ NCBI UCSC ] 2: 42996925 (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	Jul 21, 2018	Apr 16, 2018

HGVS

Nucleotide	Protein	Molecular consequence
NM_012205.3:c.558G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_036337.2:p.Trp186Ter	nonsense
NC_000002.12:g.42769785C>T
NC_000002.11:g.42996925C>T

Protein change

W186*

Other names

NM_012205.2:c.558G>A(p.Trp186Ter)

Canonical SPDI

NC_000002.12:42769784:C:T

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: CA346635341 OMIM: 604521.0002 dbSNP: rs1135401743 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.
HAAO		-	-	GRCh38 GRCh37	42	63

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.
Vertebral, cardiac, renal, and limb defects syndrome 1	Pathogenic (2)	criteria provided, single submitter	Apr 16, 2018	RCV000505813.2
Congenital NAD deficiency disorder	Pathogenic (1)	criteria provided, single submitter	Dec 23, 2016	RCV000496104.2

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.
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: SCV000540920.1 First in ClinVar: Aug 05, 2017 Last updated: Aug 05, 2017	Publications: PubMed (1) PubMed: 28792876 Comment: This variant was discovered in a consanguineous family of Middle East origin. The patient presented multiple congenital malformations affecting vertebrae, heart and kidney among others. … (more) This variant was discovered in a consanguineous family of Middle East origin. The patient presented multiple congenital malformations affecting vertebrae, heart and kidney among others. This variant is a protein truncating variant and novel (ExAC MAF 0). The patient is homozygous, while her unaffected parents and three unaffected siblings are heterozygous for this variant. The patient showed increased plasma concentration of 3HAA and reduced plasma concentration of NAD, consistent with loss of function of the HAAO enzyme activity. Enzyme assay confirmed that the protein product of this gene variant has lost enzyme activity. Mouse embryos homozygous null for Haao 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) , Vertebral segmentation defect (present) , Abnormality of the ribs (present) , Butterfly vertebrae (present) , Hypoplastic sacrum (present) , Spinal … (more) Hypoplastic left heart (present) , Vertebral segmentation defect (present) , Abnormality of the ribs (present) , Butterfly vertebrae (present) , Hypoplastic sacrum (present) , Spinal dysraphism (present) , Tethered cord (present) , Renal dysplasia (present) , Sensorineural hearing impairment (present) , Short 1st metacarpal (present) (less) Family history: no Sex: female Ethnicity/Population group: Middle East Tissue: peripheral blood lymphocytes Observation 2: Sex: mixed Tissue: plasma Method: HPLC, NAD/NADH-Gloâ„¢ Assay kit (Promega) Result: Plasma 3HAA 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: HAAO 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: Haao knockout mouse embryos showed similar phenotype as observed in the human patient
Pathogenic (Apr 16, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Vertebral, cardiac, renal, and limb defects syndrome 1 Affected status: unknown Allele origin: germline	SIB Swiss Institute of Bioinformatics Accession: SCV000787463.1 First in ClinVar: Jul 21, 2018 Last updated: Jul 21, 2018	Publications: PubMed (1) PubMed: 28792876 Comment: This variant is interpreted as a Pathogenic, for Vertebral, cardiac, renal, and limb defects syndrome 1, Autosomal Recessive inheritance. The following ACMG Tag(s) were applied: … (more) This variant is interpreted as a Pathogenic, for Vertebral, cardiac, renal, and limb defects syndrome 1, Autosomal Recessive inheritance. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PVS1-Strong => PVS1 downgraded in strength to Strong. PS3 => Well-established functional studies show a deleterious effect (PMID:28792876). (less)
Pathogenic (Sep 21, 2017)	no assertion criteria provided Method: literature only	VERTEBRAL, CARDIAC, RENAL, AND LIMB DEFECTS SYNDROME 1 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000599999.1 First in ClinVar: Sep 26, 2017 Last updated: Sep 26, 2017	Publications: PubMed (1) PubMed: 28792876 Comment on evidence: In a girl, born of consanguineous Lebanese parents (family B), with vertebral, cardiac, renal, and limb defects syndrome-1 (VCRL1; 617660), Shi et al. (2017) identified … (more) In a girl, born of consanguineous Lebanese parents (family B), with vertebral, cardiac, renal, and limb defects syndrome-1 (VCRL1; 617660), Shi et al. (2017) identified a homozygous c.558G-A transition in exon 7 of the HAAO gene, resulting in a trp186-to-ter (W186X) substitution. The mutation, which was found by whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was not found in the ExAC database and was classified as pathogenic based on the American College of Medical Genetics guidelines. In vitro functional expression studies showed that the mutation essentially abolished HAAO enzymatic activity. (less)

Comment:

This variant was discovered in a consanguineous family of Middle East origin. The patient presented multiple congenital malformations affecting vertebrae, heart and kidney among others. This variant is a protein truncating variant and novel (ExAC MAF 0). The patient is homozygous, while her unaffected parents and three unaffected siblings are heterozygous for this variant. The patient showed increased plasma concentration of 3HAA and reduced plasma concentration of NAD, consistent with loss of function of the HAAO enzyme activity. Enzyme assay confirmed that the protein product of this gene variant has lost enzyme activity. Mouse embryos homozygous null for Haao presented similar phenotype as observed in the patient, and also showed reduced concentration of NAD in the embryonic tissue.

Comment:

This variant is interpreted as a Pathogenic, for Vertebral, cardiac, renal, and limb defects syndrome 1, Autosomal Recessive inheritance. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PVS1-Strong => PVS1 downgraded in strength to Strong. PS3 => Well-established functional studies show a deleterious effect (PMID:28792876).

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) HAAO enzyme assay CRISPR/CAS9 germline knockout, mouse phenotyping	Result not provided Plasma 3HAA 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 Haao knockout mouse embryos showed similar phenotype as observed in the human patient	Embryology Laboratory, Victor Chang Cardiac Research Institute Accession: SCV000540920.1	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 rs1135401743 ...

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_012205.3(HAAO):c.558G>A (p.Trp186Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1135401743 ...