NM_014625.4(NPHS2):c.983A>G (p.Gln328Arg) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Nov 18, 2021
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:: RCV001756703.6

Allele description [Variation Report for NM_014625.4(NPHS2):c.983A>G (p.Gln328Arg)]

NM_014625.4(NPHS2):c.983A>G (p.Gln328Arg)

Genes:

NPHS2:NPHS2 stomatin family member, podocin [Gene - OMIM - HGNC]
AXDND1:axonemal dynein light chain domain containing 1 [Gene - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q25.2

Genomic location:

Preferred name:

NM_014625.4(NPHS2):c.983A>G (p.Gln328Arg)

HGVS:

NC_000001.11:g.179551342T>C
NG_007535.1:g.29608A>G
NG_033075.1:g.190623T>C
NM_001297575.2:c.779A>G
NM_014625.4:c.983A>GMANE SELECT
NM_144696.6:c.3032-3170T>CMANE SELECT
NP_001284504.1:p.Gln260Arg
NP_055440.1:p.Gln328Arg
NP_055440.1:p.Gln328Arg
LRG_887t1:c.983A>G
LRG_887:g.29608A>G
LRG_887p1:p.Gln328Arg
NC_000001.10:g.179520477T>C
NM_014625.3:c.983A>G

Protein change:

Q260R

Links:

dbSNP: rs1673239865

NCBI 1000 Genomes Browser:

rs1673239865

Molecular consequence:

NM_144696.6:c.3032-3170T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001297575.2:c.779A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_014625.4:c.983A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001986350	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Jan 28, 2019)	germline	clinical testing	Citation Link,
SCV002173681	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 18, 2021)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 14978175, 20798252, 24509478, 30260545, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001986350

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Jan 28, 2019)

germline

clinical testing

Citation Link,

SCV002173681

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Nov 18, 2021)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Patients with mutations in NPHS2 (podocin) do not respond to standard steroid treatment of nephrotic syndrome.

Ruf RG, Lichtenberger A, Karle SM, Haas JP, Anacleto FE, Schultheiss M, Zalewski I, Imm A, Ruf EM, Mucha B, Bagga A, Neuhaus T, Fuchshuber A, Bakkaloglu A, Hildebrandt F; Arbeitsgemeinschaft Für Pädiatrische Nephrologie Study Group..

J Am Soc Nephrol. 2004 Mar;15(3):722-32.

PubMed [citation]

PMID:: 14978175

Immunosuppression and renal outcome in congenital and pediatric steroid-resistant nephrotic syndrome.

Büscher AK, Kranz B, Büscher R, Hildebrandt F, Dworniczak B, Pennekamp P, Kuwertz-Bröking E, Wingen AM, John U, Kemper M, Monnens L, Hoyer PF, Weber S, Konrad M.

Clin J Am Soc Nephrol. 2010 Nov;5(11):2075-84. doi: 10.2215/CJN.01190210. Epub 2010 Aug 26. Erratum in: Clin J Am Soc Nephrol. 2012 Aug;7(8):1372-4.

PubMed [citation]

PMID:: 20798252
PMCID:: PMC3001773

See all PubMed Citations (5)

Details of each submission

From GeneDx, SCV001986350.2

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

Description

Reported previously in combination with the R229Q variant in several affected individuals (Buscher et al, 2010; Tory et al., 2014; Miko et al., 2018); Identified in the heterozygous state without a second NPHS2 variant identified in several individuals with steroid resistant nephrotic syndrome (Ruf et al., 2004; Schultheiss et al., 2004; Weber et al., 2016); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29660491, 24509478, 15338398, 26248470, 20798252, 26211502, 14978175, 30260545)

#	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, SCV002173681.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This missense change has been observed in individual(s) with clinical features of steroid-resistant nephrotic syndrome (PMID: 14978175, 20798252, 24509478, 30260545). 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 1303204). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 328 of the NPHS2 protein (p.Gln328Arg).

#	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

Last Updated: Sep 29, 2024

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