NM_020401.4(NUP107):c.2492A>C (p.Asp831Ala) AND Nephrotic syndrome, type 11

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 3, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000203507.3

Allele description [Variation Report for NM_020401.4(NUP107):c.2492A>C (p.Asp831Ala)]

NM_020401.4(NUP107):c.2492A>C (p.Asp831Ala)

Gene:

NUP107:nucleoporin 107 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

12q15

Genomic location:

Preferred name:

NM_020401.4(NUP107):c.2492A>C (p.Asp831Ala)

HGVS:

NC_000012.12:g.68735334A>C
NG_046600.2:g.53384A>C
NM_001330192.2:c.2405A>C
NM_020401.4:c.2492A>CMANE SELECT
NP_001317121.1:p.Asp802Ala
NP_065134.1:p.Asp831Ala
NC_000012.11:g.69129114A>C
NM_020401.2:c.2492A>C
P57740:p.Asp831Ala

Protein change:

D802A; ASP831ALA

Links:

UniProtKB: P57740#VAR_076359; OMIM: 607617.0001; dbSNP: rs864321632

NCBI 1000 Genomes Browser:

rs864321632

Molecular consequence:

NM_001330192.2:c.2405A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_020401.4:c.2492A>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Nephrotic syndrome, type 11 (NPHS11)
Identifiers:: MONDO: MONDO:0014752; MedGen: C4225228; Orphanet: 656; OMIM: 616730

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000258610	OMIM	no assertion criteria provided	Pathogenic (Oct 1, 2015)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV002059046	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 3, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] PMID:26411495

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000258610

OMIM

no assertion criteria provided

Pathogenic
(Oct 1, 2015)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV002059046

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 3, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

PMID:26411495

Help

Summary from all submissions

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

Citations

PubMed

Biallelic Mutations in Nuclear Pore Complex Subunit NUP107 Cause Early-Childhood-Onset Steroid-Resistant Nephrotic Syndrome.

Miyake N, Tsukaguchi H, Koshimizu E, Shono A, Matsunaga S, Shiina M, Mimura Y, Imamura S, Hirose T, Okudela K, Nozu K, Akioka Y, Hattori M, Yoshikawa N, Kitamura A, Cheong HI, Kagami S, Yamashita M, Fujita A, Miyatake S, Tsurusaki Y, Nakashima M, et al.

Am J Hum Genet. 2015 Oct 1;97(4):555-66. doi: 10.1016/j.ajhg.2015.08.013. Epub 2015 Sep 24.

PubMed [citation]

PMID:: 26411495
PMCID:: PMC4596915

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, SCV000258610.2

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

Description

In 9 affected individuals from 5 unrelated families of East Asian descent with nephrotic syndrome type 11 (NPHS11; 616730), Miyake et al. (2015) identified compound heterozygous mutations in the NUP107 gene: all patients carried c.2492A-C transversion (c.2492A-C, NM_020401.2), resulting in an asp831-to-ala (D831A) substitution at a highly conserved residue in the Nup84-Nup100 domain on 1 allele. The D831A mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the Exome Variant Server or ExAC databases, or in an in-house control database of 575 Japanese exomes, but was found at a low frequency (0.0013587) in the Human Genetic Variation Database (HGVD), a public exome database for the Japanese population. Haplotype analysis suggested a founder effect for this mutation. In vitro functional expression studies showed that the D831A mutation was localized both in the cytoplasm and the nuclear envelope, altered the C terminus, and impaired the molecular interaction between NUP107 and NUP133 (607613). The affected individuals from each family carried a different pathogenic NUP107 mutation on the other allele (607617.0002-607617.0004).

#	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, SCV002059046.1

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

Description

Same nucleotide change resulting in same amino acid change has been previously reported to be associated with NUP107 related disorder (ClinVar ID: VCV000219127, PMID:26411495, PS1_P). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 26411495, PM3_S) and it was co-segregated with Nephrotic syndrome, type 11 in multiple affected family members (PMID: 26411495, PP1_P). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (, PS3_S). A missense variant is a common mechanism associated with Nephrotic syndrome (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000012, PM2_M). 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

Last Updated: Mar 18, 2023

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