VCV002192016.3 - ClinVar

NC_000017.11:g.44001638C>T

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.

(2)

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.

Conflicting classifications of pathogenicity
Pathogenic(1); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NC_000017.11:g.44001638C>T

Variation ID: 2192016 Accession: VCV002192016.3

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17q21.31 17: 44001638 (GRCh38) [ NCBI UCSC ] 17: 42079006 (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	Feb 8, 2023	Oct 26, 2024	Aug 9, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_153006.3:c.-3026C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_004160.6:c.-463+2753G>A		intron variant
NC_000017.11:g.44001638C>T
NC_000017.10:g.42079006C>T
NG_008106.1:g.1975C>T
NG_023338.1:g.7832G>A
NG_023338.2:g.7807G>A

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000017.11:44001637:C:T

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.

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

Links

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.
NAGS		-	-	GRCh38 GRCh37	602	617
PYY		-	-	GRCh38 GRCh37	26	41

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.
Hyperammonemia, type III	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Aug 9, 2024	RCV002620899.11

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.
Uncertain significance (Sep 13, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hyperammonemia, type III Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003511940.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024	Comment: This variant occurs in a non-coding region of the NAGS gene. It does not change the encoded amino acid sequence of the NAGS protein. This … (more) This variant occurs in a non-coding region of the NAGS gene. It does not change the encoded amino acid sequence of the NAGS protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NAGS-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Pathogenic (Aug 09, 2024)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Hyperammonemia, type III Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV005380712.1 First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024	Publications: PubMed (1) PubMed: 30337552 Comment: Variant summary: NAGS c.-3026C>T is located in an enhancer in the untranscribed region upstream of the NAGS gene region. The variant allele was found at … (more) Variant summary: NAGS c.-3026C>T is located in an enhancer in the untranscribed region upstream of the NAGS gene region. The variant allele was found at a frequency of 2e-05 in 152192 control chromosomes. c.-3026C>T has been reported in the literature in three homozygous individuals affected with Hyperammonemia, type III from two different families (Williams_2018). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating the impact of the variant on NAGS expression using a reporter gene assay in HepG2 cells. The variant resulted in a modest but significant decrease in NAGS expression, exhibiting approximately 80% NAGS expression versus the wild-type NAGS enhancer.The following publication has been ascertained in the context of this evaluation (PMID: 30337552). ClinVar contains an entry for this variant (Variation ID: 2192016). Based on the evidence outlined above, the variant was classified as pathogenic. (less)

Comment:

This variant occurs in a non-coding region of the NAGS gene. It does not change the encoded amino acid sequence of the NAGS protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NAGS-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

Variant summary: NAGS c.-3026C>T is located in an enhancer in the untranscribed region upstream of the NAGS gene region. The variant allele was found at a frequency of 2e-05 in 152192 control chromosomes. c.-3026C>T has been reported in the literature in three homozygous individuals affected with Hyperammonemia, type III from two different families (Williams_2018). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating the impact of the variant on NAGS expression using a reporter gene assay in HepG2 cells. The variant resulted in a modest but significant decrease in NAGS expression, exhibiting approximately 80% NAGS expression versus the wild-type NAGS enhancer.The following publication has been ascertained in the context of this evaluation (PMID: 30337552). ClinVar contains an entry for this variant (Variation ID: 2192016). Based on the evidence outlined above, the variant was classified 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
N-Acetylglutamate Synthase Deficiency Due to a Recurrent Sequence Variant in the N-acetylglutamate Synthase Enhancer Region.	Williams M	Scientific reports	2018	PMID: 30337552

Text-mined citations for this variant ...

Record last updated Nov 03, 2024

ClinVar Genomic variation as it relates to human health

NC_000017.11:g.44001638C>T

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...