VCV000259482.23 - ClinVar

NM_004646.4(NPHS1):c.1223G>A (p.Arg408Gln)

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.

(13)

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.

Benign/Likely benign

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_004646.4(NPHS1):c.1223G>A (p.Arg408Gln)

Variation ID: 259482 Accession: VCV000259482.23

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19q13.12 19: 35848345 (GRCh38) [ NCBI UCSC ] 19: 36339247 (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	Oct 3, 2016	Sep 29, 2024	Feb 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_004646.4:c.1223G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004637.1:p.Arg408Gln	missense
NC_000019.10:g.35848345C>T
NC_000019.9:g.36339247C>T
NG_013356.2:g.25943G>A
NG_051206.1:g.1711C>T
LRG_693:g.25943G>A
LRG_693t1:c.1223G>A	LRG_693p1:p.Arg408Gln
	O60500:p.Arg408Gln

... more HGVS ... less HGVS

Protein change

R408Q

Other names

NM_004646.3(NPHS1):c.1223G>A(p.Arg408Gln)

Canonical SPDI

NC_000019.10:35848344: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.

0.02057 (T)

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

1000 Genomes Project 0.02057

1000 Genomes Project 30x 0.02264

Trans-Omics for Precision Medicine (TOPMed) 0.03992

The Genome Aggregation Database (gnomAD) 0.04436

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.04621

Exome Aggregation Consortium (ExAC) 0.04733

The Genome Aggregation Database (gnomAD), exomes 0.04874

Links

ClinGen: CA9390498 UniProtKB: O60500#VAR_013041 dbSNP: rs33950747 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.
NPHS1		-	-	GRCh38 GRCh37	1674	1858

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.
not specified	Benign (2)	criteria provided, single submitter	-	RCV000251573.7
Finnish congenital nephrotic syndrome	Benign (5)	criteria provided, multiple submitters, no conflicts	Jun 10, 2021	RCV000277714.9
not provided	Benign/Likely benign (4)	criteria provided, multiple submitters, no conflicts	Feb 1, 2024	RCV000712420.11
Congenital nephrotic syndrome	Likely benign (1)	criteria provided, single submitter	Mar 6, 2018	RCV001094492.4
Atypical hemolytic-uremic syndrome	Benign (1)	criteria provided, single submitter	Oct 9, 2021	RCV002294138.2

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.
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000310559.1 First in ClinVar: Oct 03, 2016 Last updated: Oct 03, 2016
Likely benign (Mar 06, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Congenital nephrotic syndrome Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000411576.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. (less)
Benign (Jul 20, 2015)	criteria provided, single submitter (ACGS Guidelines, 2013) Method: clinical testing	Finnish congenital nephrotic syndrome Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Study: VKGL Data-share Consensus Accession: SCV000743921.1 First in ClinVar: Apr 19, 2018 Last updated: Apr 19, 2018
Benign (May 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Finnish congenital nephrotic syndrome Affected status: unknown Allele origin: unknown	SIB Swiss Institute of Bioinformatics Accession: SCV000803437.1 First in ClinVar: May 03, 2018 Last updated: May 03, 2018	Comment: This variant is interpreted as a Benign - Stand Alone, for Nephrotic syndrome, type 1, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: … (more) This variant is interpreted as a Benign - Stand Alone, for Nephrotic syndrome, type 1, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BA1 => Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. (less)
Benign (Aug 23, 2017)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV000842912.1 First in ClinVar: Oct 20, 2018 Last updated: Oct 20, 2018	Publications: PubMed (2) PubMed: 11317351‚ 9915943
Benign (Jun 10, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Finnish congenital nephrotic syndrome Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV001738131.1 First in ClinVar: Jun 24, 2021 Last updated: Jun 24, 2021	Sex: mixed
Benign (Oct 15, 2019)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001860434.1 First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021	Comment: This variant is associated with the following publications: (PMID: 31216994, 27884173, 9915943, 21228398, 20981092, 20507940, 11726550, 24742477)
Benign (Oct 09, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Atypical hemolytic-uremic syndrome Affected status: unknown Allele origin: germline	Genome Diagnostics Laboratory, The Hospital for Sick Children Accession: SCV002587634.1 First in ClinVar: Oct 29, 2022 Last updated: Oct 29, 2022
Benign (Feb 01, 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: SCV001719671.4 First in ClinVar: Jun 15, 2021 Last updated: Feb 20, 2024
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005207021.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (-)	no assertion criteria provided Method: clinical testing	Finnish congenital nephrotic syndrome Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV000733876.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018
Benign (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Finnish congenital nephrotic syndrome Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001460542.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001952621.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
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Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

Comment:

This variant is interpreted as a Benign - Stand Alone, for Nephrotic syndrome, type 1, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BA1 => Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.

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
Mutation spectrum in the nephrin gene (NPHS1) in congenital nephrotic syndrome.	Beltcheva O	Human mutation	2001	PMID: 11317351
Structure of the gene for congenital nephrotic syndrome of the finnish type (NPHS1) and characterization of mutations.	Lenkkeri U	American journal of human genetics	1999	PMID: 9915943

Text-mined citations for rs33950747 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_004646.4(NPHS1):c.1223G>A (p.Arg408Gln)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs33950747 ...