VCV000224964.18 - ClinVar

NM_014669.5(NUP93):c.1772G>T (p.Gly591Val)

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_014669.5(NUP93):c.1772G>T (p.Gly591Val)

Variation ID: 224964 Accession: VCV000224964.18

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 16q13 16: 56834768 (GRCh38) [ NCBI UCSC ] 16: 56868680 (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 9, 2016	Oct 20, 2024	Sep 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_014669.5:c.1772G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_055484.3:p.Gly591Val	missense
NM_001242795.2:c.1403G>T	NP_001229724.1:p.Gly468Val	missense
NM_001242796.2:c.1403G>T	NP_001229725.1:p.Gly468Val	missense
NC_000016.10:g.56834768G>T
NC_000016.9:g.56868680G>T
NG_052904.1:g.109664G>T
	Q8N1F7:p.Gly591Val

... more HGVS ... less HGVS

Protein change

G591V, G468V

Other names

Canonical SPDI

NC_000016.10:56834767:G: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.

Exome Aggregation Consortium (ExAC) 0.00012

The Genome Aggregation Database (gnomAD), exomes 0.00012

The Genome Aggregation Database (gnomAD) 0.00014

Trans-Omics for Precision Medicine (TOPMed) 0.00014

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015

Links

ClinGen: CA357847 UniProtKB: Q8N1F7#VAR_076474 OMIM: 614351.0001 dbSNP: rs145473779 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.
NUP93		-	-	GRCh38 GRCh37	246	270

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.
Nephrotic syndrome, type 12	Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Sep 1, 2024	RCV000210563.8
not provided	Pathogenic/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Mar 1, 2024	RCV001799635.13
Nephrotic syndrome	Likely pathogenic (1)	no assertion criteria provided	Nov 10, 2017	RCV001849346.1

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.
Likely pathogenic (Dec 10, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002043967.2 First in ClinVar: Jan 01, 2022 Last updated: Mar 04, 2023	Comment: Published functional studies demonstrate a damaging effect; this variant fails to interact and reduces translocation of SMAD4 (Braun et al., 2016); In silico analysis supports … (more) Published functional studies demonstrate a damaging effect; this variant fails to interact and reduces translocation of SMAD4 (Braun et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function and splicing; This variant is associated with the following publications: (PMID: 31517150, 30577294, 26878725, 33578576, 29869118, 33532864) (less)
Pathogenic (Jan 22, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002233611.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 26878725 Comment: This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 591 of the NUP93 protein (p.Gly591Val). … (more) This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 591 of the NUP93 protein (p.Gly591Val). This variant is present in population databases (rs145473779, gnomAD 0.03%). This missense change has been observed in individual(s) with steroid-resistant nephrotic syndrome (PMID: 26878725). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 224964). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NUP93 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects NUP93 function (PMID: 26878725). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. (less)
Likely pathogenic (Feb 01, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Nephrotic syndrome, type 12 Affected status: yes Allele origin: inherited	Molecular Biology Laboratory, Fundació Puigvert Study: KidneyPanel_2020 Accession: SCV001425128.1 First in ClinVar: Jan 17, 2021 Last updated: Jan 17, 2021	Publications: PubMed (1) PubMed: 33532864
Likely pathogenic (Sep 01, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Nephrotic syndrome, type 12 (Autosomal recessive inheritance) Affected status: yes Allele origin: maternal	Precision Medicine Center, Zhengzhou University Accession: SCV004218461.2 First in ClinVar: Jun 23, 2024 Last updated: Sep 29, 2024	Comment: PM2_p,PM3,PS3 Sex: male
Likely pathogenic (Mar 01, 2024)	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: SCV004811113.7 First in ClinVar: Apr 15, 2024 Last updated: Oct 20, 2024	Comment: NUP93: PM3:Strong, PM2:Supporting, PP3, PS3:Supporting Number of individuals with the variant: 1
Pathogenic (May 30, 2018)	no assertion criteria provided Method: clinical testing	Nephrotic syndrome, type 12 Affected status: yes Allele origin: germline	Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare Accession: SCV000863893.1 First in ClinVar: Dec 24, 2018 Last updated: Dec 24, 2018
Pathogenic (Nov 20, 2020)	no assertion criteria provided Method: literature only	NEPHROTIC SYNDROME, TYPE 12 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000266815.2 First in ClinVar: Apr 09, 2016 Last updated: Nov 26, 2020	Publications: PubMed (1) PubMed: 26878725 Comment on evidence: In 2 sibs, born of consanguineous Turkish parents, with nephrotic syndrome type 12 (NPHS12; 616892), Braun et al. (2016) identified a homozygous c.1772G-T transversion (c.1772G-T, … (more) In 2 sibs, born of consanguineous Turkish parents, with nephrotic syndrome type 12 (NPHS12; 616892), Braun et al. (2016) identified a homozygous c.1772G-T transversion (c.1772G-T, NM_014669.4) in exon 16 of the NUP93 gene, resulting in a gly591-to-val (G591V) substitution at a highly conserved residue in the beta-propeller region. The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing, segregated with the disorder in the family. The family was from a cohort of 160 families with steroid-resistant nephrotic syndrome (SRNS). Subsequent analysis of 1,800 additional families with SRNS identified 3 who were compound heterozygous for G591V and another pathogenic mutation in the NUP93 gene (614351.0003-614351.0005). The other 3 families were of German or Serbian descent. In vitro functional expression studies showed that the G591V mutant protein localized normally to the nuclear envelope and could restore nuclear envelope and nuclear pore complex assembly in NUP93-depleted Xenopus egg extracts. However, the mutation abrogated the normal interaction of NUP93 with the phosphorylated, activated forms of SMAD1 (601595) and SMAD5 (603110) and with the nuclear import receptor IPO7 (605586), and impaired BMP7 (112267)/SMAD4 (600993)-dependent gene transcription. (less)
Likely pathogenic (Nov 10, 2017)	no assertion criteria provided Method: literature only	Nephrotic syndrome Affected status: yes Allele origin: germline	Yale Center for Mendelian Genomics, Yale University Study: Yale Center for Mendelian Genomics Accession: SCV002107013.1 First in ClinVar: Mar 28, 2022 Last updated: Mar 28, 2022	Publications: PubMed (1) PubMed: 29127259

Comment:

Published functional studies demonstrate a damaging effect; this variant fails to interact and reduces translocation of SMAD4 (Braun et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function and splicing; This variant is associated with the following publications: (PMID: 31517150, 30577294, 26878725, 33578576, 29869118, 33532864)

Comment:

This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 591 of the NUP93 protein (p.Gly591Val). This variant is present in population databases (rs145473779, gnomAD 0.03%). This missense change has been observed in individual(s) with steroid-resistant nephrotic syndrome (PMID: 26878725). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 224964). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NUP93 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects NUP93 function (PMID: 26878725). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been 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
Clinical utility of genetic testing in early-onset kidney disease: seven genes are the main players.	Domingo-Gallego A	Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association	2022	PMID: 33532864
Whole Exome Sequencing of Patients with Steroid-Resistant Nephrotic Syndrome.	Warejko JK	Clinical journal of the American Society of Nephrology : CJASN	2018	PMID: 29127259
Mutations in nuclear pore genes NUP93, NUP205 and XPO5 cause steroid-resistant nephrotic syndrome.	Braun DA	Nature genetics	2016	PMID: 26878725

Text-mined citations for rs145473779 ...

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_014669.5(NUP93):c.1772G>T (p.Gly591Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs145473779 ...