VCV000056431.18 - ClinVar

NM_004646.4(NPHS1):c.121_122del (p.Leu41fs)

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.

(12)

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

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.121_122del (p.Leu41fs)

Variation ID: 56431 Accession: VCV000056431.18

Type and length

Deletion, 2 bp

Location

Cytogenetic: 19q13.12 19: 35851609-35851610 (GRCh38) [ NCBI UCSC ] 19: 36342511-36342512 (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 4, 2013	Jun 17, 2024	Jan 16, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_004646.4:c.121_122del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004637.1:p.Leu41fs	frameshift
NM_004646.3:c.121_122delCT
NC_000019.10:g.35851609_35851610del
NC_000019.9:g.36342511_36342512del
NG_013356.2:g.22678_22679del
NG_051206.1:g.4975_4976del
LRG_693:g.22678_22679del
LRG_693t1:c.121_122del	LRG_693p1:p.Leu41fs

... more HGVS ... less HGVS

Protein change

L41fs

Other names

Canonical SPDI

NC_000019.10:35851608:AG:

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.

Trans-Omics for Precision Medicine (TOPMed) 0.00001

The Genome Aggregation Database (gnomAD) 0.00089

Exome Aggregation Consortium (ExAC) 0.00101

The Genome Aggregation Database (gnomAD), exomes 0.00108

Links

OMIM: 602716.0001 dbSNP: rs386833873 ClinGen: CA344732 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.
KIRREL2		-	-	GRCh38 GRCh37	51	231
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.
Finnish congenital nephrotic syndrome	Pathogenic (9)	criteria provided, multiple submitters, no conflicts	Nov 2, 2023	RCV000049844.13
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jan 16, 2024	RCV000681697.8
NPHS1-related disorder	Pathogenic (1)	criteria provided, single submitter	Jun 13, 2023	RCV003415817.5

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.
Pathogenic (May 20, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Finnish congenital nephrotic syndrome Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002782440.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Jun 13, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NPHS1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004118421.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The NPHS1 c.121_122delCT variant is predicted to result in a frameshift and premature protein termination (p.Leu41Aspfs50). This small deletion has been reported to be causative … (more) The NPHS1 c.121_122delCT variant is predicted to result in a frameshift and premature protein termination (p.Leu41Aspfs50). This small deletion has been reported to be causative for congenital nephrotic syndrome and was documented as one of two typical Finnish pathogenic NPHS1 variants (Kestilä et al. 1998. PubMed ID: 9660941; Lenkkeri et al. 1999. PubMed ID: 9915943). This variant is reported in 1.1% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-36342510-CAG-C). Frameshift variants in NPHS1 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
Pathogenic (Dec 15, 2016)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Finnish congenital nephrotic syndrome Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000698495.1 First in ClinVar: Feb 06, 2015 Last updated: Feb 06, 2015	Comment: Variant summary: The NPHS1 c.121_122delCT (p.Leu41Aspfs) variant results in a premature termination codon, predicted to cause a truncated or absent NPHS1 protein due to nonsense … (more) Variant summary: The NPHS1 c.121_122delCT (p.Leu41Aspfs) variant results in a premature termination codon, predicted to cause a truncated or absent NPHS1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant of interest is a Finnish founder mutation known as Fin-major. The variant of interest has been found in the large, broad control population, ExAC, with an allele frequency of 114/113010, predominantly in the Finnish cohort, 80/5484, which is expected since the variant is indicated to be a Finnish founder mutation. The variant of interest has been reported in multiple affected individuals as homozygous and compound heterozygous. In addition, multiple clinical diagnostic laboratories/databases cite the variant as "pathogenic." Therefore, the variant of interest has been classified as "pathogenic." (less)
Pathogenic (Sep 16, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	not provided Affected status: yes Allele origin: germline	Gharavi Laboratory, Columbia University Accession: SCV000809146.1 First in ClinVar: Sep 30, 2018 Last updated: Sep 30, 2018
Pathogenic (Dec 20, 2019)	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019)) Method: clinical testing	Finnish congenital nephrotic syndrome Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV001193991.2 First in ClinVar: Apr 06, 2020 Last updated: Jul 06, 2020	Publications: PubMed (3) PubMed: 9660941‚ 9915943‚ 23949594 Comment: NM_004646.3(NPHS1):c.121_122delCT(L41Dfs50, aka Fin major) is classified as pathogenic in the context of NPHS1-related nephrotic syndrome. Sources cited for classification include the following: PMID 9660941, 9915943 … (more) NM_004646.3(NPHS1):c.121_122delCT(L41Dfs50, aka Fin major) is classified as pathogenic in the context of NPHS1-related nephrotic syndrome. Sources cited for classification include the following: PMID 9660941, 9915943 and 23949594. Classification of NM_004646.3(NPHS1):c.121_122delCT(L41Dfs*50, aka Fin major) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. (less)
Pathogenic (Nov 02, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Finnish congenital nephrotic syndrome Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004191421.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Jan 16, 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: SCV000931674.6 First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 11317351‚ 11854170‚ 12039988‚ 9660941‚ 9915943 Comment: This sequence change creates a premature translational stop signal (p.Leu41Aspfs50) in the NPHS1 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Leu41Aspfs50) in the NPHS1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NPHS1 are known to be pathogenic (PMID: 11317351, 11854170, 12039988). This variant is present in population databases (rs386833873, gnomAD 1.1%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with nephrotic syndrome, and is a common founder mutation in the Finnish population (PMID: 9660941, 9915943). It is commonly reported in individuals of Finnish ancestry (PMID: 9660941, 9915943). This variant is also known as "Fin major". ClinVar contains an entry for this variant (Variation ID: 56431). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Mar 01, 1998)	no assertion criteria provided Method: literature only	NEPHROTIC SYNDROME, TYPE 1 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000027465.2 First in ClinVar: Apr 04, 2013 Last updated: Jul 07, 2022	Publications: PubMed (1) PubMed: 9660941 Comment on evidence: Kestila et al. (1998) found a 2-nucleotide deletion (121delCT) in exon 2 of the nephrin gene in many Finnish patients with steroid-resistant congenital nephrotic syndrome … (more) Kestila et al. (1998) found a 2-nucleotide deletion (121delCT) in exon 2 of the nephrin gene in many Finnish patients with steroid-resistant congenital nephrotic syndrome (NPHS1; 256300). Of 49 patients studied, 32 were homozygotes for this mutation, and 8 were compound heterozygotes. The mutation results in a frameshift and a truncated protein. All patients shared a common founder haplotype of polymorphic sites. This mutation has been referred to as Fin(major). (less)
pathogenic (-)	no assertion criteria provided Method: not provided	Finnish congenital nephrotic syndrome Affected status: not provided Allele origin: unknown	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) Accession: SCV000082253.1 First in ClinVar: Jul 24, 2013 Last updated: Jul 24, 2013 Comment: FinDis database variant: This variant was not found or characterized by our laboratory, data were collected from public sources: see reference	Comment: Converted during submission to Pathogenic.
Pathogenic (Jan 06, 2020)	no assertion criteria provided Method: curation	Finnish congenital nephrotic syndrome Affected status: unknown Allele origin: germline	Reproductive Health Research and Development, BGI Genomics Accession: SCV001142487.1 First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020	Comment: NM_004646.3:c.121_122delCT in the NPHS1 gene is also known as Fin-major in publications. It has an allele frequency of 0.011 in European (Finnish) subpopulation in the … (more) NM_004646.3:c.121_122delCT in the NPHS1 gene is also known as Fin-major in publications. It has an allele frequency of 0.011 in European (Finnish) subpopulation in the gnomAD database. The NPHS1 c.121_122delCT (p.Leu41Aspfs) variant locates at the 2nd exon out of 29 exons of the biological transcript of NPHS1. It results in a premature termination codon, predicting to cause a truncated or absent NPHS1 protein due to nonsense mediated decay. Lenkkeri et al reported one American congenital Nephrotic Syndrome patient was a heterozygote for the Fin-major mutation, carrying a single base insertion in exon 24 of the other allele (PMID: 9915943). This variant also has been observed in many individuals with nephrotic syndrome, and is a common founder mutation in the Finnish population (PMID: 9660941; 9915943). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PVS1; PS4; PM3; PP4. (less)
Pathogenic (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Finnish congenital nephrotic syndrome Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001461579.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
Pathogenic (Oct 17, 2014)	no assertion criteria provided Method: clinical testing	Finnish congenital nephrotic syndrome Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV000207134.1 First in ClinVar: Feb 06, 2015 Last updated: Feb 06, 2015	Publications: PubMed (1) PubMed: 9660941 Number of individuals with the variant: 2
click to load more click to collapse

Comment:

The NPHS1 c.121_122delCT variant is predicted to result in a frameshift and premature protein termination (p.Leu41Aspfs*50). This small deletion has been reported to be causative for congenital nephrotic syndrome and was documented as one of two typical Finnish pathogenic NPHS1 variants (Kestilä et al. 1998. PubMed ID: 9660941; Lenkkeri et al. 1999. PubMed ID: 9915943). This variant is reported in 1.1% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-36342510-CAG-C). Frameshift variants in NPHS1 are expected to be pathogenic. This variant is interpreted as pathogenic.

Comment:

Variant summary: The NPHS1 c.121_122delCT (p.Leu41Aspfs) variant results in a premature termination codon, predicted to cause a truncated or absent NPHS1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant of interest is a Finnish founder mutation known as Fin-major. The variant of interest has been found in the large, broad control population, ExAC, with an allele frequency of 114/113010, predominantly in the Finnish cohort, 80/5484, which is expected since the variant is indicated to be a Finnish founder mutation. The variant of interest has been reported in multiple affected individuals as homozygous and compound heterozygous. In addition, multiple clinical diagnostic laboratories/databases cite the variant as "pathogenic." Therefore, the variant of interest has been classified as "pathogenic."

Comment:

NM_004646.3(NPHS1):c.121_122delCT(L41Dfs*50, aka Fin major) is classified as pathogenic in the context of NPHS1-related nephrotic syndrome. Sources cited for classification include the following: PMID 9660941, 9915943 and 23949594. Classification of NM_004646.3(NPHS1):c.121_122delCT(L41Dfs*50, aka Fin major) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.

Comment:

This sequence change creates a premature translational stop signal (p.Leu41Aspfs*50) in the NPHS1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NPHS1 are known to be pathogenic (PMID: 11317351, 11854170, 12039988). This variant is present in population databases (rs386833873, gnomAD 1.1%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with nephrotic syndrome, and is a common founder mutation in the Finnish population (PMID: 9660941, 9915943). It is commonly reported in individuals of Finnish ancestry (PMID: 9660941, 9915943). This variant is also known as "Fin major". ClinVar contains an entry for this variant (Variation ID: 56431). For these reasons, this variant has been classified as Pathogenic.

Comment:

NM_004646.3:c.121_122delCT in the NPHS1 gene is also known as Fin-major in publications. It has an allele frequency of 0.011 in European (Finnish) subpopulation in the gnomAD database. The NPHS1 c.121_122delCT (p.Leu41Aspfs) variant locates at the 2nd exon out of 29 exons of the biological transcript of NPHS1. It results in a premature termination codon, predicting to cause a truncated or absent NPHS1 protein due to nonsense mediated decay. Lenkkeri et al reported one American congenital Nephrotic Syndrome patient was a heterozygote for the Fin-major mutation, carrying a single base insertion in exon 24 of the other allele (PMID: 9915943). This variant also has been observed in many individuals with nephrotic syndrome, and is a common founder mutation in the Finnish population (PMID: 9660941; 9915943). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PVS1; PS4; PM3; PP4.

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
Congenital nephrotic syndrome with prolonged renal survival without renal replacement therapy.	Wong W	Pediatric nephrology (Berlin, Germany)	2013	PMID: 23949594
Nephrin TRAP mice lack slit diaphragms and show fibrotic glomeruli and cystic tubular lesions.	Rantanen M	Journal of the American Society of Nephrology : JASN	2002	PMID: 12039988
Genotype/phenotype correlations of NPHS1 and NPHS2 mutations in nephrotic syndrome advocate a functional inter-relationship in glomerular filtration.	Koziell A	Human molecular genetics	2002	PMID: 11854170
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
Positionally cloned gene for a novel glomerular protein--nephrin--is mutated in congenital nephrotic syndrome.	Kestilä M	Molecular cell	1998	PMID: 9660941

Text-mined citations for rs386833873 ...

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.121_122del (p.Leu41fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs386833873 ...