NM_004646.4(NPHS1):c.1019C>A (p.Pro340His) AND Finnish congenital nephrotic syndrome

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Mar 12, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000049830.4

Allele description [Variation Report for NM_004646.4(NPHS1):c.1019C>A (p.Pro340His)]

NM_004646.4(NPHS1):c.1019C>A (p.Pro340His)

Gene:

NPHS1:NPHS1 adhesion molecule, nephrin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19q13.12

Genomic location:

Preferred name:

NM_004646.4(NPHS1):c.1019C>A (p.Pro340His)

HGVS:

NC_000019.10:g.35848788G>T
NG_013356.2:g.25500C>A
NG_051206.1:g.2154G>T
NM_004646.4:c.1019C>AMANE SELECT
NP_004637.1:p.Pro340His
NP_004637.1:p.Pro340His
LRG_693t1:c.1019C>A
LRG_693:g.25500C>A
LRG_693p1:p.Pro340His
NC_000019.9:g.36339690G>T
NM_004646.3:c.1019C>A
O60500:p.Pro340His

Protein change:

P340H

Links:

UniProtKB: O60500#VAR_064202; dbSNP: rs386833861

NCBI 1000 Genomes Browser:

rs386833861

Molecular consequence:

NM_004646.4:c.1019C>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Finnish congenital nephrotic syndrome (NPHS1)
Synonyms:: NEPHROTIC SYNDROME, TYPE 1; Nephrosis 1, congenital, Finnish type; Congenital nephrotic syndrome 1
Identifiers:: MONDO: MONDO:0009732; MedGen: C0403399; Orphanet: 839; OMIM: 256300

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000082239	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	no assertion criteria provided	probable-pathogenic	not provided	not provided	PubMed (1) [See all records that cite this PMID]
SCV001164372	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Dec 3, 2018)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV005053646	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 12, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000082239

Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)

no assertion criteria provided

probable-pathogenic

not provided

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

SCV001164372

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Dec 3, 2018)

germline

research

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

SCV005053646

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Mar 12, 2024)

unknown

clinical testing

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

Description

FinDis database variant: FinDis database variant: This variant was not found or characterized by our laboratory, data were collected from public sources: see reference: SCV000082239

Help

Summary from all submissions

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

Citations

PubMed

Nineteen novel NPHS1 mutations in a worldwide cohort of patients with congenital nephrotic syndrome (CNS).

Schoeb DS, Chernin G, Heeringa SF, Matejas V, Held S, Vega-Warner V, Bockenhauer D, Vlangos CN, Moorani KN, Neuhaus TJ, Kari JA, MacDonald J, Saisawat P, Ashraf S, Ovunc B, Zenker M, Hildebrandt F; Gesselschaft für Paediatrische Nephrologie (GPN) Study Group..

Nephrol Dial Transplant. 2010 Sep;25(9):2970-6. doi: 10.1093/ndt/gfq088. Epub 2010 Feb 18.

PubMed [citation]

PMID:: 20172850
PMCID:: PMC2948833

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 Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM), SCV000082239.1

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

Description

Converted during submission to Likely pathogenic.

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

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001164372.1

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

Description

The homozygous p.Pro340His variant in NPHS1 was identified by our study in one individual with nephrotic syndrome. The p.Pro340His variant in NPHS1 has not been previously reported in individuals with nephrotic syndrome and has been identified in 0.009746% (3/30782) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs386833861). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Pro340His variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3 (Richards 2015).

#	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 Baylor Genetics, SCV005053646.1

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

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

Last Updated: Jun 17, 2024

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