NM_014669.5(NUP93):c.1772G>T (p.Gly591Val) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Mar 1, 2024
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:: RCV001799635.13

Allele description [Variation Report for NM_014669.5(NUP93):c.1772G>T (p.Gly591Val)]

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

Gene:

NUP93:nucleoporin 93 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16q13

Genomic location:

Preferred name:

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

HGVS:

NC_000016.10:g.56834768G>T
NG_052904.1:g.109664G>T
NM_001242795.2:c.1403G>T
NM_001242796.2:c.1403G>T
NM_014669.5:c.1772G>TMANE SELECT
NP_001229724.1:p.Gly468Val
NP_001229725.1:p.Gly468Val
NP_055484.3:p.Gly591Val
NC_000016.9:g.56868680G>T
NM_014669.4:c.1772G>T
Q8N1F7:p.Gly591Val

Protein change:

G468V; GLY591VAL

Links:

UniProtKB: Q8N1F7#VAR_076474; OMIM: 614351.0001; dbSNP: rs145473779

NCBI 1000 Genomes Browser:

rs145473779

Molecular consequence:

NM_001242795.2:c.1403G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001242796.2:c.1403G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_014669.5:c.1772G>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Caenorhabditis elegans Peptidase S72 domain-containing protein (dgn-2), partial ...
Caenorhabditis elegans Peptidase S72 domain-containing protein (dgn-2), partial mRNA
gi|17568230|ref|NM_075852.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002043967	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Dec 10, 2021)	germline	clinical testing	Citation Link,
SCV002233611	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 22, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26878725, 28492532
SCV004811113	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Likely pathogenic (Mar 1, 2024)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002043967

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely pathogenic
(Dec 10, 2021)

germline

clinical testing

Citation Link,

SCV002233611

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 22, 2024)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV004811113

CeGaT Center for Human Genetics Tuebingen

criteria provided, single submitter

(CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)

Likely pathogenic
(Mar 1, 2024)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutations in nuclear pore genes NUP93, NUP205 and XPO5 cause steroid-resistant nephrotic syndrome.

Braun DA, Sadowski CE, Kohl S, Lovric S, Astrinidis SA, Pabst WL, Gee HY, Ashraf S, Lawson JA, Shril S, Airik M, Tan W, Schapiro D, Rao J, Choi WI, Hermle T, Kemper MJ, Pohl M, Ozaltin F, Konrad M, Bogdanovic R, Büscher R, et al.

Nat Genet. 2016 Apr;48(4):457-65. doi: 10.1038/ng.3512. Epub 2016 Feb 15.

PubMed [citation]

PMID:: 26878725
PMCID:: PMC4811732

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From GeneDx, SCV002043967.2

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

Description

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)

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002233611.3

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

Description

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.

#	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 CeGaT Center for Human Genetics Tuebingen, SCV004811113.7

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

Description

NUP93: PM3:Strong, PM2:Supporting, PP3, PS3:Supporting

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

Last Updated: Oct 20, 2024

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