NM_018161.5(NADSYN1):c.1717G>A (p.Ala573Thr) AND Vertebral, cardiac, renal, and limb defects syndrome 3

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: May 10, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001035449.13

Allele description [Variation Report for NM_018161.5(NADSYN1):c.1717G>A (p.Ala573Thr)]

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

Gene:

NADSYN1:NAD synthetase 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11q13.4

Genomic location:

Preferred name:

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

HGVS:

NC_000011.10:g.71491856G>A
NM_018161.5:c.1717G>AMANE SELECT
NP_060631.2:p.Ala573Thr
NC_000011.9:g.71202902G>A
NM_018161.4:c.1717G>A

Protein change:

A573T; ALA573THR

Links:

OMIM: 608285.0001; dbSNP: rs144139747

NCBI 1000 Genomes Browser:

rs144139747

Molecular consequence:

NM_018161.5:c.1717G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Vertebral, cardiac, renal, and limb defects syndrome 3
Synonyms:: CONGENITAL NAD DEFICIENCY DISORDER 3
Identifiers:: MONDO: MONDO:0030077; MedGen: C5394250; OMIM: 618845

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001198776	OMIM	no assertion criteria provided	Pathogenic (Apr 10, 2020)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV002572736	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 1, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31883644, 25741868
SCV003816251	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 14, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004025912	Embryology Laboratory, Victor Chang Cardiac Research Institute	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 10, 2023)	maternal, biparental, paternal	research	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	maternal	yes	1	not provided	not provided	1	not provided	research
not provided	biparental	yes	4	not provided	not provided	4	not provided	research
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	paternal	yes	1	not provided	not provided	1	not provided	research

Citations

PubMed

Bi-allelic Mutations in NADSYN1 Cause Multiple Organ Defects and Expand the Genotypic Spectrum of Congenital NAD Deficiency Disorders.

Szot JO, Campagnolo C, Cao Y, Iyer KR, Cuny H, Drysdale T, Flores-Daboub JA, Bi W, Westerfield L, Liu P, Leung TN, Choy KW, Chapman G, Xiao R, Siu VM, Dunwoodie SL.

Am J Hum Genet. 2020 Jan 2;106(1):129-136. doi: 10.1016/j.ajhg.2019.12.006. Epub 2019 Dec 26.

PubMed [citation]

PMID:: 31883644
PMCID:: PMC7042491

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From OMIM, SCV001198776.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From 3billion, SCV002572736.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (2)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV003816251.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Embryology Laboratory, Victor Chang Cardiac Research Institute, SCV004025912.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	research	PubMed (1)
2	not provided	1	not provided	not provided	research	PubMed (1)
3	not provided	1	not provided	not provided	research	PubMed (1)
4	not provided	1	not provided	not provided	research	PubMed (1)
5	not provided	1	not provided	not provided	research	PubMed (1)
6	not provided	1	not provided	not provided	research	PubMed (1)

Description

This variant was found in compound heterozygosity with the likely pathogenic variant c.1759G>A.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	maternal	yes	1	not provided	not provided		1	not provided	not provided	not provided
2	biparental	yes	1	not provided	not provided		1	not provided	not provided	not provided
3	biparental	yes	1	not provided	not provided		1	not provided	not provided	not provided
4	biparental	yes	1	not provided	not provided		1	not provided	not provided	not provided
5	biparental	yes	1	not provided	not provided		1	not provided	not provided	not provided
6	paternal	yes	1	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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