VCV000834710.39 - ClinVar

NM_018161.5(NADSYN1):c.1717G>A (p.Ala573Thr)

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.

(8)

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/Likely 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_018161.5(NADSYN1):c.1717G>A (p.Ala573Thr)

Variation ID: 834710 Accession: VCV000834710.39

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11q13.4 11: 71491856 (GRCh38) [ NCBI UCSC ] 11: 71202902 (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	Apr 15, 2020	Oct 20, 2024	Dec 1, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_018161.5:c.1717G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_060631.2:p.Ala573Thr	missense
NM_018161.4:c.1717G>A
NC_000011.10:g.71491856G>A
NC_000011.9:g.71202902G>A

Protein change

A573T

Other names

Canonical SPDI

NC_000011.10:71491855:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

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.

0.00020 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

Trans-Omics for Precision Medicine (TOPMed) 0.00076

The Genome Aggregation Database (gnomAD) 0.00081

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00131

Links

OMIM: 608285.0001 dbSNP: rs144139747 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.
NADSYN1		-	-	GRCh38 GRCh37	103	116

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 3	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	May 10, 2023	RCV001035449.13
Congenital NAD deficiency disorder	Pathogenic (1)	no assertion criteria provided	Dec 1, 2019	RCV001078184.8
not provided	Pathogenic (1)	criteria provided, single submitter	Dec 1, 2023	RCV001532179.25
Neurodevelopmental delay	Pathogenic (1)	criteria provided, single submitter	-	RCV002274118.9
NADSYN1-related disorder	Pathogenic (1)	no assertion criteria provided	Nov 28, 2023	RCV003963002.2

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 (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neurodevelopmental delay Affected status: yes Allele origin: biparental	Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille Accession: SCV002559108.1 First in ClinVar: Aug 15, 2022 Last updated: Aug 15, 2022
Pathogenic (Sep 01, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Vertebral, cardiac, renal, and limb defects syndrome 3 Affected status: yes Allele origin: germline	3billion Accession: SCV002572736.1 First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022	Publications: PubMed (1) PubMed: 31883644 Comment: The missense variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.074%). Functional studies provide strong evidence that … (more) The missense variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.074%). Functional studies provide strong evidence that the variant has a damaging effect on the gene or gene product (PMID: 31883644). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with NADSYN1 -related disorder (ClinVar ID: VCV000834710 / PMID: 31883644). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual, and co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID: 31883644). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Abnormal cardiovascular system morphology (present) , Fused cervical vertebrae (present) , Abnormal thoracic spine morphology (present) , Spina bifida (present) , Relatively short spine (present) … (more) Abnormal cardiovascular system morphology (present) , Fused cervical vertebrae (present) , Abnormal thoracic spine morphology (present) , Spina bifida (present) , Relatively short spine (present) , Scoliosis (present) , Congenital elevation of scapula (present) , Joint laxity (present) (less)
Pathogenic (May 10, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Vertebral, cardiac, renal, and limb defects syndrome 3 (Autosomal recessive inheritance) Affected status: yes Allele origin: maternal, biparental, paternal	Embryology Laboratory, Victor Chang Cardiac Research Institute Accession: SCV004025912.1 First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024	Comment: This variant was found in compound heterozygosity with the likely pathogenic variant c.1759G>A. Observation 1: Observation 2: Observation 3: Observation 4: Observation 5: Observation 6:
Likely pathogenic (Oct 14, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Vertebral, cardiac, renal, and limb defects syndrome 3 Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003816251.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Pathogenic (Dec 01, 2023)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001747615.20 First in ClinVar: Jul 10, 2021 Last updated: Oct 20, 2024	Comment: NADSYN1: PM3:Very Strong, PM2, PS3:Supporting Number of individuals with the variant: 6
Pathogenic (Apr 10, 2020)	no assertion criteria provided Method: literature only	VERTEBRAL, CARDIAC, RENAL, AND LIMB DEFECTS SYNDROME 3 Affected status: not provided Allele origin: germline	OMIM Accession: SCV001198776.1 First in ClinVar: Apr 15, 2020 Last updated: Apr 15, 2020	Publications: PubMed (1) PubMed: 31883644 Comment on evidence: In 2 sibs (family 1) with vertebral, cardiac, renal, and limb abnormalities (VCRL3; 618845), Szot et al. (2020) identified homozygosity for a c.1717G-A transition (c.1717G-A, … (more) In 2 sibs (family 1) with vertebral, cardiac, renal, and limb abnormalities (VCRL3; 618845), Szot et al. (2020) identified homozygosity for a c.1717G-A transition (c.1717G-A, NM_018161.5) in the NADSYN1 gene, resulting in an ala573-to-thr (A573T) substitution at a highly conserved residue within the P2 loop of the NAD synthetase domain. Their unaffected parents were heterozygous for the mutation. Using GeneMatcher, the authors identified a similarly affected male infant (family 2) who was compound heterozygous for the A573T mutation and a 1-bp deletion (c.1819del; 608285.0002), causing a frameshift predicted to result in a premature termination codon (Val607TrpfsTer30). His unaffected parents were each heterozygous for 1 of the mutations. The A573T and c.1819del mutations were both present at low minor allele frequency in the gnomAD database (7.40 x 10(-4) and 7.07 x 10(-6), respectively). In yeast complementation assays, the A573T mutant showed an 86% decrease in total cellular NAD compared to wildtype NADSYN1. Enzymatic assays in transfected COS7 cells showed an approximately 342-fold reduction in NAD synthetase-specific activity with the mutant compared to wildtype protein. (less)
Pathogenic (Dec 01, 2019)	no assertion criteria provided Method: research	Congenital NAD Deficiency Disorder (Autosomal recessive inheritance) Affected status: yes Allele origin: inherited	Embryology Laboratory, Victor Chang Cardiac Research Institute Accession: SCV001244270.1 First in ClinVar: Apr 24, 2020 Last updated: Apr 24, 2020	Publications: PubMed (1) PubMed: 31883644 Comment: This variant, c.1717G>A, was identified in two homozgyous children (male and female) of the same family. This variant was also found in compound heterozygosity with … (more) This variant, c.1717G>A, was identified in two homozgyous children (male and female) of the same family. This variant was also found in compound heterozygosity with the pathogenic variant c.1819del in a different family (less) Observation 1: Sex: male Observation 2: Sex: female Observation 3: Sex: male
Pathogenic (Nov 28, 2023)	no assertion criteria provided Method: clinical testing	NADSYN1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004779426.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: The NADSYN1 c.1717G>A variant is predicted to result in the amino acid substitution p.Ala573Thr. This variant has been reported in both the homozygous and compound … (more) The NADSYN1 c.1717G>A variant is predicted to result in the amino acid substitution p.Ala573Thr. This variant has been reported in both the homozygous and compound heterozygous states to be causative for autosomal recessive vertebral, cardiac, renal, and limb defects syndrome 3, and functional studies support its pathogenicity (VCRL3; OMIM #618845; Szot et al. 2020. PubMed ID: 31883644; Kortbawi et al. 2022. PubMed ID: 35491967). In addition, we have observed this variant in the homozygous state in multiple individuals with features consistent with VCRL3 at PreventionGenetics. In summary, we interpret this variant as pathogenic. (less)

Comment:

The missense variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.074%). Functional studies provide strong evidence that the variant has a damaging effect on the gene or gene product (PMID: 31883644). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with NADSYN1 -related disorder (ClinVar ID: VCV000834710 / PMID: 31883644). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual, and co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID: 31883644). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

The NADSYN1 c.1717G>A variant is predicted to result in the amino acid substitution p.Ala573Thr. This variant has been reported in both the homozygous and compound heterozygous states to be causative for autosomal recessive vertebral, cardiac, renal, and limb defects syndrome 3, and functional studies support its pathogenicity (VCRL3; OMIM #618845; Szot et al. 2020. PubMed ID: 31883644; Kortbawi et al. 2022. PubMed ID: 35491967). In addition, we have observed this variant in the homozygous state in multiple individuals with features consistent with VCRL3 at PreventionGenetics. In summary, we interpret this variant 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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
A metabolic signature for NADSYN1-dependent congenital NAD deficiency disorder.	Szot JO	The Journal of clinical investigation	2024	PMID: 38357931
Bi-allelic Mutations in NADSYN1 Cause Multiple Organ Defects and Expand the Genotypic Spectrum of Congenital NAD Deficiency Disorders.	Szot JO	American journal of human genetics	2020	PMID: 31883644

Text-mined citations for rs144139747 ...

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 Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_018161.5(NADSYN1):c.1717G>A (p.Ala573Thr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs144139747 ...